Novel compounds and pharmaceutical compositions thereof for the treatment of infectious diseases

Abstract

The present invention discloses compounds according to Formula (I) wherein X, L1, R1 and Cy are as defined herein. Herein are disclosed compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and / or treatment of diseases involving tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM).

Description

NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFECTIOUS DISEASESFIELD

[0001] Herein are provided inter alia, compounds that may be useful in the prophylaxis and / or treatment of tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM). Herein is also provided methods for the production of the compound of the invention, pharmaceutical compositions comprising the compound of the invention, methods for the prophylaxis and / or treatment of NTM by administering the compound of the invention.BACKGROUND

[0002] Tuberculosis (TB) is a contagious and deadly disease caused by Mycobacterium tuberculosis (MTB), that has reached pandemic proportions: 8 - 10 million new cases of tuberculosis (TB) are diagnosed each year, leading to death in adults (2-3 million / year) according to the World Health Organization (WHO).

[0003] In addition to TB, recent epidemiological studies have shown the emergence of non-tuberculous mycobacteria (NTM) species in causing lung diseases in humans. Non-tuberculous mycobacteria (NTM) are referred to as atypical mycobacteria and are defined as mycobacteria other than Mycobacterium (M). leprae and M. tuberculosis (MTB) with its close relatives, M. africanum, M. bovis, M. canetti and caprae.

[0004] Although more than 170 NTM species (Gopalaswamy et al. 2020) are present in various environmental niches, only a handful, primarily M avium complex and M abscessus, have been implicated in pulmonary disease causing opportunistic infections in humans with pre-existing conditions, particularly in individuals with suppressed immune systems or underlying structural lung damage such as bronchiectasis, cystic fibrosis (CF), Chronic Obstructive Pulmonary Disease (COPD), or asthma, and patients with other diseases such as HIV and diabetes are at high risk of contracting pulmonary NTM disease. NTM disease is mostly disseminated through aerosols originated from the environment (Gopalaswamy et al. 2020).

[0005] The incidence and number of deaths from NTM disease have steadily increased globally, especially in developed countries (Prevots and Marras 2015). However, early patient diagnosis is challenging due to non-specific symptoms in patients, which may result in underestimation of the overall incidence.

[0006] Although the pathophysiology of TB and NTM diseases share several fundamental cellular and molecular events, the host-susceptibility to MTB and NTM infections are different.

[0007] In general, drug-sensitive TB is treated with a standard multi-drug regimen containing well-defined first- and second-line antibiotics (Gopalaswamy et al. 2020).

[0008] In contrast, the NTM species display significant heterogeneity in their susceptibility to standard anti-TB drugs. Thus, the treatment for NTM diseases usually involves inter alia, the use of macrolides and injectable aminoglycosides. Although well-established international guidelines are available, treatment of NTM disease is mostly empirical, poorly tolerated and is successful in only a proportion of patients. In general, the treatment duration is much longer for NTM diseases (18-24 months), compared to TB, andresection surgery of affected organ(s) is part of treatment for patients with NTM diseases that do not respond to the antibiotic treatment. (Daley et al. 2020; Gopalaswamy et al. 2020).

[0009] In fighting TB and / or NTM, the rifamycins (RIFs) are the most commonly used drugs despite serious drawbacks including: Cyp450 induction, which is particularly problematic for HIV-MTB coinfection, and the existence of resistant mutations that yield RIF-resistant (RIFR) MTB strains. In addition, certain detoxification pathways are present in some NTM species which render rifamycins inactive.

[0010] Semisynthetic rifamycin derivatives including rifampin, rifalazil (RLZ), rifapentine (RFP), and rifabutin (RFB) appear to show improved antimycobacterial activities. However, all RIFs are ineffective against the most prevalent RIFR MTB mutant (rpoB S450L) (Tuberculosis (2008) 88(2) 148-150), and a major downside to using rifamycins to treat TB is their many drug -drug interactions due to extremely potent activation of the human pregnane X receptor (hPXR) leading to a dramatic induction of CYP2C9, CYP3A4 and other hepatic metabolizing enzymes and transporters.

[0011] The long and toxic treatment, the raise of resistance, the worldwide increasing prevalence and the high hospital costs makes TB and / or NTM infections a high unmet medical need for which new drugs are desperately needed.SUMMARY

[0012] There is a need for new compounds which are not associated with the disadvantages of prior compounds, to provide new treatments and methods of prophylaxis, and / or treatment of TB and / or NTM.

[0013] As such, herein are provided inter alia, compounds that may be useful in the prophylaxis and / or treatment of TB and / or NTM. In particular, the compounds provided herein may show improved potency against TB and / or NTM, reduced toxicity, and / or improved PK / PD profile.

[0014] In some aspects, herein are also provided methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and / or treatment of TB and / or NTM by administering the compounds of the invention.

[0015] Accordingly, in a first aspect of the invention, the compounds of the invention or pharmaceutically acceptable salts, or solvates, or the salts of a solvate thereof, are provided having a Formula (I):WhereinX is absent, O, or -NR2-;Li is absent, or C1-4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3, where the N heteroatoms may optionally be oxidized,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3;C1-4 alkyl optionally substituted with one or more groups independently selected from =0 and R3a; R2is H, C1-4 alkyl, or C3-5 monocyclic cycloalkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4groups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4group,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more independently selected R4; Each R3and R3ais independently selected from:halo,CN, or- -YA-LA-R5;Each R4is independently selected from:halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from:absent,Ci-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA and LB is independently selected from:absent,- -0-,- -(C=0),- -C(=0)0-,- -C(=NH)NR7a-,- -C(=0)NR7a-,- -C(=O)NR7a-C(=O)-,- -S(=0)-,- -S(=0)2-,- -S(=O)2NR7b-,- -NR7fS(=O)2-,- -NR7CC(=0)-,- -P(=O)R7d-,- -NR7e-,- -P(=O)(OR7d)O-,- -C(=O)NR7fS(=O)2-,- -C(=0)NR7f-0-,- -C(=O)-C(=O)NR7f-,- -0C(=0)-NR7b-,- -OC(=O)-,- -S(=O)(=NR7b)-,- -OP(=O)(OR7d)O-,- -NR7CC(=0)0-,Each R5, R6, R7a, R7b, R7c, R7d, R7eand R7fis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl, pyridinyl, deuterium, -C(=0)NHCH3, -NHC(=0) CH3, or cyclopropyl,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or moreindependently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,3-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, - S(=O)2-cyclopropyl, -C(=O)OCH3, -S(=O)2CH3, -C(=O)-cyclopropyl, -P(=O)(CH3)2, -C(=0)0H, -N(CH3)2, CN, -C(=0)NHCH3, -NHC(=0)-CH3, -C(=0)NH2, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo; where the N heteroatoms of said heteroaryl may optionally be oxidized.

[0016] Accordingly, in a further aspect of the invention, the compounds of the invention are provided having a Formula (I):WhereinX is absent, O, or -NR2- Li is absent, or C1-4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R3;R2is H, Ci-4 alkyl or C3-5 monocyclic cycloalkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4groups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4group,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4;Each R3is independently selected from:halo,CN, or- -YA-LA-R5;Each R4is independently selected from:halo,- =0,CN, or- -YB-LB-R6,Each YA and YB is independently selected from:absentCi-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA and LB is independently selected fromabsent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -S(=O)-,- -S(=O)2-,- -NR7fS(=O)2-,- -S(=O)2NR7b-,- -NR7CC(=O)-,- -P(=O)R7d-, and- -NR7e-;Each R5, R6, R7a, R7b, R7c, R7d, R7eand R7fis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,4-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo.

[0017] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of TB and / or NTM.

[0018] Furthermore, it has also been unexpectedly demonstrated that the compounds of the invention exhibit improved drug -drug interaction (DDI) profile.

[0019] In a further aspect, herein are also provided pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient, or diluent. In a particular aspect, the pharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of TB and / or NTM.

[0020] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0021] In a further aspect, this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly TB and / or NTM, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.

[0022] The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and / or treatment of TB and / or NTM.

[0023] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0024] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.DETAILED DESCRIPTIONDefinitions

[0025] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope.

[0026] When describing inter alia compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0027] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.

[0028] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), n-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2-CH2-CH2-CH3), tert-butyl (-CH2-C(CH3)3), sec-butyl (-CH2-CH(CH3)2), n-pentyl (-CH2-CH2-CH2-CH2-CH3), n-hexyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0029] ‘Alkenyl’ refers to monovalent olefmically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), isopropenyl (-C(CH3)=CH2) and the like.

[0030] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2-), or -CH(CH3)- and the like.

[0031] ‘Alkynylene’ refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C=C-, -CH2-C=C-, and -C(CH3)H-C=CH-.

[0032] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-Ci e alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0033] ‘ Amino’ refers to the radical -NH2.

[0034] ‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0035] ‘Cycloalkyl’ refers to non-aromatic fully or partially saturated ring structure, monocyclic, fused polycyclic, spirocyclic or bridged polycyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. When partially saturated, the cycloalkyl may contain one or two double bonds, and more particularly onedouble bond. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Such polycyclic and / or partially saturated cycloalkyl groups include, by way of example:

[0036] ‘Cyano’ refers to the radical -CN.

[0037] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0038] ‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0039] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. The nitrogen and sulphur heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quatemized. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0040] “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heteroaryl bicyclic ring systems can be vicinally fused, i.e., where the rings are linked to each other through two adjacent carbon and / or nitrogen atoms. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-l, 2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 1,3-dihydroisobenzofuran, 2,3-dihydro-benzo[ 1,4] dioxinyl, benzofl, 3]dioxolyl, 2,2-dioxo-l,3-dihydro-2-benzothienyl, 4, 5, 6, 7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro- 1, 8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-6][l,4]oxazinyl.

[0041] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0042] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0043] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0044] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0045] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0046] Examples of representative heteroaryls include the following:wherein each Y is selected from > C=O, NH, O and S.

[0047] ‘Heterocycloalkyl’ means a non-aromatic fully or partially saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N, P, Se, Si, B, and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, phosphorus, sulfur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. When partially saturated, the heterocycloalkyl may contain one or two double bonds, and more particularly one double bond. Examples of heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1-tetrahydrofuranyl, 2-tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1-tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3 -tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl,2-piperidinyl, 3-piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl), tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0048] Particular examples of monocyclic rings are shown in the following illustrative examples:wherein each Wand Y is independently selected from -CH2-, -NH-, -O-, -Si-, -Se-, -BH-, -B-OH, -Si(CH3)2-, and -S-.

[0049] Particular examples of fused bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O-, Si-, -Se-, -BH-, -B-OH, -Si(CH3)2-, and -S-.

[0050] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:wherein each Wand Y is independently selected from -CH2-, -NH-, -O-, -Si-, -Se-, -BH-, -B-OH, -Si(CH3)2-, and — S- and each Z is selected from N or CH.

[0051] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, -O-, -Si-, -Se-, -BH-, -B-OH, -Si(CH3)2-, and -S-.

[0052] Particular examples of monocyclic partially saturated heterocycloalkyl rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O-, and -S-, and Z is P, N, or CH.

[0053] ‘hydrocarbon chain’ refers to an organic molecule consisting of nothing else but carbon and hydrogen atoms arranged in a chain, which carbon and hydrogen atoms are interconnected to each other by covalent bonding. Each carbon atom in the chain is bonded to one or up to three hydrogen atoms, hydrocarbon chains may be classified as branched, linear, or cyclical. They may also be divided into alkanes, alkenes, alkynes, cycloalkanes, and aryls. A hydrocarbon chain may also be classified as either saturated or unsaturated, or aliphatic or aromatic. A saturated hydrocarbon chain is saturated with hydrogenwhereas an unsaturated hydrocarbon chain is one in which hydrogen atom can still be added in the chain by breaking the double-bond (alkene) or triple bond (alkyne) between carbon atoms.

[0054] ‘Hydroxyl’ refers to the radical -OH.

[0055] ‘ Oxo’ refers to the radical =0.

[0056] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0057] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as -SO3H.

[0058] ‘ Thiol’ refers to the group -SH.

[0059] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In one embodiment it refers to one to three substituents. In further embodiments it refers to one or two substituents. In a yet further embodiment it refers to one substituent.

[0060] ‘Thioalkoxy’ refers to the group -S-alkyl where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -S-C1-6 alkyl. Particular thioalkoxy groups are thiomethoxy, thioethoxy, n-thiopropoxy, isothiopropoxy, n-thiobutoxy, tert-thiobutoxy, sec-thiobutoxy, n-thiopentoxy, n-thiohexoxy, and 1,2-dimethylthiobutoxy. Particular thioalkoxy groups are lower thioalkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0061] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0062] ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U. S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0063] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid,glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g. an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0064] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0065] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0066] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0067] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0068] ‘ Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0069] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0070] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0071] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0072] As used herein the term tuberculosis (TB) diseases refers to the group of conditions caused by the mycobacterium tuberculosis (MTB), affecting primarily the lungs, but also inter alia, the bones, lymph nodes, bone marrow (miliary TB), liver, heart, genitourinary and gastrointestinal tract, meninges (meningeal tuberculosis) and / or the skin.

[0073] As used herein the term non-tuberculous mycobacteria (NTM) disease, also known as environmental mycobacteria, atypical mycobacteria and mycobacteria other than MTB (MOTT), diseases refers to the group of conditions are mycobacteria which do not cause tuberculosis or leprosy (also known as Hansen's disease). NTM do cause pulmonary diseases that resemble tuberculosis. The most common clinical manifestation of NTM disease is lung disease, but lymphatic, skin / soft tissue, and disseminated diseases, which can affect nearly all organs are also important.

[0074] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[0075] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.

[0076] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (Ce-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.

[0077] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixtureof mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature ( referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0078] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (11C), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulphur-35 (35S), chlorine-36 (36Cl), chlorine-37 (37Cl), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0079] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon-14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e.2H or D may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such as11C,18F,15O and13N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0080] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.

[0081] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively).A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.

[0082] ‘ Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.

[0083] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0084] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0085] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0086] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.EMBODIMENTS

[0087] Herein are provided inter alia, compounds that may be useful in the prophylaxis and / or treatment of NTM. In some aspects, herein are also provided methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, methods for the prophylaxis and / or treatment of NTM by administering the compounds of the invention.

[0088] Accordingly, in a first aspect of the invention, the compounds of the invention or pharmaceutically acceptable salts, or solvates, or the salts of a solvate thereof, are provided having a Formula (I):WhereinX is absent, O, or -NR2-;Li is absent, or C1.4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3, where the N heteroatoms may optionally be oxidized,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3;Ci-4 alkyl optionally substituted with one or more groups independently selected from =0 and R3a; R2is H, Ci-4 alkyl, or C3-5 monocyclic cycloalkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4groups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4group,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more independently selected R4; Each R3and R3ais independently selected from:halo,CN, or- -YA-LA-R5;Each R4is independently selected from:halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from:absent,Ci-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA and LB is independently selected from:absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -C(=O)NR7a-C(=O)-,- -S(=O)-,- -S(=O)2-,- -S(=O)2NR7b-,- -NR7fS(=O)2-,- -NR7CC(=O)-,- -P(=O)R7d-,- -NR7e-,- -P(=O)(OR7d)O-,- -C(=O)NR7fS(=O)2-,- -C(=O)NR7f-O-,- -C(=O)-C(=O)NR7f-,- -OC(=O)-NR7b-,- -OC(=O)-,- -S(=O)(=NR7b)-,- -OP(=O)(OR7d)O-,- -NR7CC(=O)O-,Each R5, R6, R7a, R7b, R7c, R7d, R7eand R7fis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl, pyridinyl, deuterium, -C(=0)NHCH3, -NHC(=O) CH3, or cyclopropyl,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,3-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, - S(=O)2-cyclopropyl, -C(=O)OCH3, -S(=O)2CH3, -C(=O)-cyclopropyl, -P(=O)(CH3)2, -C(=0)0H, -N(CH3)2, CN, -C(=0)NHCH3, -NHC(=0)-CH3, -C(=0)NH2, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo; where the N heteroatoms of said heteroaryl may optionally be oxidized.

[0089] In another particular aspect, the compound of the invention is according to Formula I, wherein X is absent, O, or -NR2-;Li is absent, or C1-4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3, where the N heteroatoms may optionally be oxidized,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3;Ci-4 alkyl optionally substituted with one or more groups independently selected from =0 and R3a; R2is H, Ci-4 alkyl, or C3-5 monocyclic cycloalkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4groups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4group,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more independently selected R4; Each R3and R3ais independently selected from:halo,CN, or- -YA-LA-R5;Each R4is independently selected from:halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from:absent,C1-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA and LB is independently selected from:absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=0)NR7a-,- -C(=O)NR7a-C(=O)-,- -S(=O)-,- -S(=0)2-,- -S(=O)2NR7b-,- -NR7fS(=O)2-,- -NR7CC(=O)-,- -P(=O)R7d-,- -NR7e-;Each R5, R6, R7a, R7b, R7c, R7d, R7eand R7fis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl, or pyridinyl;3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,3-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, - S(=O)2-cyclopropyl, -C(=O)OCH3, -S(=O)2CH3, -C(=O)-cyclopropyl, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo; where the N heteroatoms of said heteroaryl may optionally be oxidized.

[0090] In another particular aspect, the compound of the invention is according to Formula I, wherein X is absent, O, or -NR2- Li is absent, or C1-4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3,5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3;R2is H, Ci-4 alkyl or C3-5 monocyclic cycloalkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4groups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4group,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4;Each R3is independently selected from:halo,CN, or- -YA-LA-R5;Each R4is independently selected from:halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from:absent,Ci-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA and LB is independently selected from:absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -S(=O)-,- -S(=O)2-,- -S(=O)2NR7b-,- -NR7fS(=O)2-,- -NR7CC(=O)-,- -P(=O)R7d-, and- -NR7e-;Each R5, R6, R7a, R7b, R7c, R7d, R7eand R7fis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,3-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo.

[0091] In another particular aspect, the compound of the invention is according to Formula I, wherein X is absent, O, or -NR2- Li is absent, or C1.4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3,3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R3;R2is H or C1.4 alkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4groups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4group,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is optionally substituted with one or more independently selected R4;Each R3is independently selected from:halo,CN, or- -YA-LA-R5;Each R4is independently selected from:halo,- =0,CN, or- -YB-LB-R6,Each YA and YB is independently selected from:absentCi-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA and LB is independently selected fromabsent,- -0-,- -(C=0),- -C(=0)0-,- -C(=NH)NR7a-,- -C(=0)NR7a-,- -S(=0)-,- -S(=0)2-,- -S(=O)2NR7b-,- -NR7CC(=0)-,- -P(=O)R7d-,- -NR7e-;Each R5, R6, R7a, R7b, R7c, R7d, and R7eis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl,4-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo,4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, Ci-4 alkyl optionally substituted with one or more independently selected halo, or Ci-4 alkoxy optionally substituted with one or more independently selected halo,6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo.

[0092] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4groups. In a particular embodiment, Cy is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one, two or three independently selected R4group. In a more particular embodiment, Cy is pyrrolidinyl, or piperidinyl, each of which is substituted with one, two or three independently selected R4group. In a more particular embodiment, Cy is pyrrolidinyl, or piperidinyl, each of which is substituted with one R4group.

[0093] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is C3-7 cycloalkyl monocyclic optionally substituted with one or more independently selected R4groups. In a particular embodiment, Cy is C3-7 cycloalkyl monocyclic optionally substituted with one, two or three independently selected R4group. In a more particular embodiment, Cy is cyclopentyl or cyclohexyl, each of which is substituted with one, two or three independently selected R4group. In a more particular embodiment, Cy is cyclopentyl or cyclohexyl, each of which is substituted with one R4group.

[0094] In one embodiment, the compound of the invention is according to Formula II:Wherein X, Li, R1and R4are as described for Formula I.

[0095] In one embodiment, the compound of the invention is according to Formula I or II, wherein R4is -YB-LB-R6, wherein YB, LB, and R6are as described for Formula I. In a particular embodiment, YB is C1-4 alkylene, LB and R6is as described for Formula I. In a more particular embodiment, YB is C1-4 alkylene, LB is absent and R6is as described for Formula I. In a further more particular embodiment, YB is C1-4 alkylene, LB is absent and R6is H.

[0096] In one embodiment, the compound of the invention is according to Formula I or II, wherein R4is -YB-LB-R6, YB is C1-4 alkylene, LB is absent and R6is C1-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl, or pyridinyl. In a most particular embodiment, R4is -CH2CH2CH3. or -CH2CH(CH3)2.

[0097] In one embodiment, the compound of the invention is according to Formula I or II, wherein R4is -YB-LB-R6, YB is C1-4 alkylene, LB is absent and R6is 3-7 membered monocyclic cycloalkyl. In a most particular embodiment, R4is -CH2-Cyclopropyl.

[0098] In one embodiment, the compound of the invention is according to Formula I or II, wherein R4is -YB-LB-R6, YB is C1-4 alkylene, LB is O, or -C(=O)NR7a, R6and R7aare as described for Formula I. In yet a further more particular embodiment, YB is C1-4 alkylene, LB is O, or -C(=O)NR7a, R6and R7aare H. In a most particular embodiment, R4is -CH2CH2CH2OH, -CH2CH(CH3)CH2OH, -CH2C(=O)NH2, -CH2CH2CH2C(=O)NH2, -CH2CH(CH3)CH2C(=O)NH2.

[0099] In one embodiment, the compound of the invention is according to Formula I or II, wherein R4is selected from the group comprising -CH2CH(CH3)2-CH2CH2CH3, -CH2-Cyclopropyl, -CH2CH2CH2OH, -CH2CH(CH3)CH2OH, -CH2C(=O)NH2, -CH2CH2CH2C(=O)NH2, and -CH2CH(CH3)CH2C(=O)NH2.

[0100] In one embodiment, the compound of the invention is according to Formula I, wherein Cy is selected from:wherein * represents the points of attachment.

[0101] In one embodiment, the compound of the invention is according to Formula III:wherein X, Li, and R1are as described for Formula I.

[0102] In one embodiment, the compound of the invention is according to Formula III, whereinX is absent, O, or -NR2-;Li is absent, or C1-4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3, where the N heteroatoms may optionally be oxidized;8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3;3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3;C1-4 alkyl optionally substituted with one or more groups independently selected from =0 and R3a; R2is H, C1-4 alkyl, or C3-5 monocyclic cycloalkyl;Each R3and R3ais independently selected from:halo,CN, or- -YA-LA-R5;Each YA is independently selected from:absent,C1-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA is independently selected from:absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=0)NR7a-,- -C(=O)NR7a-C(=O)-,- -S(=0)-,- -S(=0)2-,- -S(=O)2NR7b-,- -NR7fS(=O)2-,- -NR7CC(=O)-,- -P(=O)R7d-,- -NR7e-;Each R5, R7a, R7b, R7c, R7d, R7eand R7fis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl, or pyridinyl,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,3-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, - S(=O)2-cyclopropyl, -C(=O)OCH3, -S(=O)2CH3, -C(=O)-cyclopropyl, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, - C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo; where the N heteroatoms of said heteroaryl may optionally be oxidized.

[0103] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein X is absent.

[0104] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein X is O.

[0105] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein X is -NR2-, and R2is as described for Formula I. In a particular embodiment, R2is H, or -CH3. In a particular embodiment, R2is H. In another particular embodiment, R2is cyclopropyl.

[0106] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein Li is absent.

[0107] In one embodiment, the compound of the invention is according to Formula I, II or III, wherein Li is C1.4 alkylene. In a particular embodiment, Li is -CH2-.

[0108] In one embodiment, the compound of the invention is according to Formula IVa, or IVb:wherein R1is as described for Formula I.

[0109] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is phenyl optionally substituted with one or more independently selected R3. In a particular embodiment, R1is phenyl optionally substituted with one, two or three independently selected R3. In a particular embodiment, R1is phenyl optionally substituted with one or two independently selected R3. In a particular embodiment, R1is phenyl optionally substituted with one R3.

[0110] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3, where the N heteroatoms may optionally be oxidized. In a particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one, two or three independently selected R3, where the N heteroatoms may optionally be oxidized. In a particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or two independently selected R3, where the N heteroatoms may optionally be oxidized. In a particular embodiment, R1is 5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one R3, where the N heteroatoms may optionally be oxidized.

[0111] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, or pyrazolopyrimidinyl, for example wherein R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl,

[0112] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, or pyrazolopyrimidinyl, each of which is substituted with one or more independently selected R3, where the N heteroatoms may optionally be oxidized. In a particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, or pyrazolopyrimidinyl, each of which is substituted with one, two or three independently selected R3, where the N heteroatoms may optionally be oxidized. In a particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, or pyrazolopyrimidinyl, each of which is substituted with one or two independently selected R3, where the N heteroatoms may optionally be oxidized. In a particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, or pyrazolopyrimidinyl, each of which is substituted with one R3, where the N heteroatoms may optionally be oxidized.

[0113] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected R3. In a particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one, two or three independently selected R3. In a particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or two independently selected R3. In a particular embodiment, R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one R3.

[0114] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3. In a particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one, two or three independently selected R3. In a particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or two independently selected R3. In a particular embodiment, R1is 8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one R3.

[0115] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is indazolyl, indazolyl, isoindolinyl, benzofuranyl, benzothiazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, benzoxazolyl, quinolinyl, or quinazolinyl.

[0116] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is indazolyl, indazolyl, isoindolinyl, benzofuranyl, benzothiazolyl, triazolopyridinyl,tetrahydrobenzoisoxazolyl, benzoxazolyl, quinolinyl, or quinazolinyl, each of which is substituted with one or more independently selected R3. In a particular embodiment, R1is indazolyl, indazolyl, isoindolinyl, benzofuranyl, benzothiazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, benzoxazolyl, quinolinyl, or quinazolinyl, each of which is substituted with one, two or three independently selected R3. In a particular embodiment, R1is indazolyl, indazolyl, isoindolinyl, benzofuranyl, benzothiazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, benzoxazolyl, quinolinyl, or quinazolinyl, each of which is substituted with one or two independently selected R3. In a particular embodiment, R1is indazolyl, indazolyl, isoindolinyl, benzofuranyl, benzothiazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, benzoxazolyl, quinolinyl, or quinazolinyl, each of which is substituted with one R3.

[0117] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is 3-7 membered monocyclic cycloalkyl optionally substituted with one, two or three groups independently selected from =0 and R3. In a particular embodiment, R1is 3-7 membered monocyclic cycloalkyl optionally substituted with one or two groups independently selected from =0 and R3. In a particular embodiment, R1is 3-7 membered monocyclic cycloalkyl optionally substituted with one group independently selected from =0 and R3.

[0118] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0119] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one, two or three groups independently selected from =0 and R3. In a particular embodiment, R1is 3 cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or two groups independently selected from =0 and R3. In a particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one group independently selected from =0 and R3.

[0120] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is 5-12 membered bicyclic fused, bridged or spiro cycloalkyl optionally substituted with one, two or three groups independently selected from =0 and R3. In a particular embodiment, R1is 5-12 membered bicyclic fused, bridged or spiro cycloalkyl optionally substituted with one or two groups independently selected from =0 and R3. In a particular embodiment, R1is 5-12 membered bicyclic fused, bridged or spiro cycloalkyl optionally substituted with one group independently selected from =0 and R3.

[0121] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl.

[0122] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is bicyclo [l.l.l]pentanyl, bicyclo [2. l.l]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is optionally substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is bicyclo [l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2. l]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3,3]heptanyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R3. In a particular embodiment, R1is bicyclo[l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is optionally substituted with one or two groups independently selected from =0 and R3. In a particular embodiment, R1is bicyclo [l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2. l]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3,3]heptanyl, each of which is optionally substituted with one group independently selected from =0 and R3.

[0123] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is bicyclo[1.1.1]pentanyl, bicyclo[2.1. l]hexanyl, bicyclo[2.2. l]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is bicyclo [l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3. In a particular embodiment, R1is bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is substituted with one or two groups independently selected from =0 and R3. In a particular embodiment, R1is bicyclo [l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2. l]heptanyl, bicyclo[2.2.2]octanyl, or spiro[3.3]heptanyl, each of which is substituted with one group independently selected from =0 and R3.

[0124] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one, two or three independently selected R3. In a particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one or two independently selected R3. In a particular embodiment, R1is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one R3.

[0125] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl.

[0126] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is optionally substituted with one or moregroups independently selected from =0 and R3. In a particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is optionally substituted with one, two or three independently selected R3. In a particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is optionally substituted with one or two independently selected R3. In a particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is optionally substituted with one R3.

[0127] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is substituted with one, two or three independently selected R3. In a particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is substituted with one or two independently selected R3. In a particular embodiment, R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is substituted with one R3.

[0128] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one, two or three groups independently selected from =0 and R3. In a particular embodiment, R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one or two groups independently selected from =0 and R3. In a particular embodiment, R1is 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one groups independently selected from =0 and R3.

[0129] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, l,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro [4.5] decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl.

[0130] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl, each of which is optionally substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7 -oxa-2 -azaspiro [3,5]nonanyl, 2-oxa-6-azaspiro[3,3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R3. In a particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, l,3,8-triazaspiro[4.5]decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl, each of which is optionally substituted with one or two groups independently selected from =0 and R3. In a particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl, each of which is optionally substituted with one groups independently selected from =0 and R3.

[0131] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl, each of which is substituted with one or more groups independently selected from =0 and R3. In a particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl, each of which is substituted with one, two or three groups independently selected from =0 and R3. In a particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, l,3,8-triazaspiro[4.5]decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl, each of which is substituted with one or two groups independently selected from =0 and R3. In a particular embodiment, R1is 2,5-dioxaspiro[3.5]nonanyl, octahydropyrrolo[3,2-b]pyrrolyl, 7 -oxa-2 -azaspiro [3,5]nonanyl, 2-oxa-6-azaspiro[3,3]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 4-oxa-7-azaspiro[2.5]octanyl, 6-azaspiro[2.5]octanyl, 2,5-dioxa-8-azaspiro[3.5]nonanyl, 5-azaspiro[2.4]heptane, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 2-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 2-oxaspiro[3.3]heptanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, diazepanyl, or oxazepanyl, each of which is substituted with one groups independently selected from =0 and R3.

[0132] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is Ci-4 alkyl optionally substituted with one or more, preferably with one, two or three groups independently selected from =0 and R3a.

[0133] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is Ci-4 alkyl substituted with one, two or three groups independently selected from =0 and R3a.

[0134] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is Ci-4 alkyl, and one or more independently selected R3ais -YA-LA-R5.

[0135] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is Ci-4 alkyl, and one or more independently selected R3ais -YA-LA-R5, wherein YA is absent and LA is selected from the group comprising -(C=0), -C(=0)0-, -C(=NH)NR7a-, -C(=0)NR7a-, -NR7CC(=0)-, and -NR7e-.

[0136] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is C1-4 alkyl, and one or more independently selected R3ais -YA-LA-R5, wherein YA is absent and LA is selected from the group comprising -(C=O), -C(=O)NR7a-, -NR7cC(=O)-, and -NR7e-.

[0137] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is C1-4 alkyl, and one or more independently selected R3ais -YA-LA-R5, wherein YA is absent and LA is selected from the group comprising -(C=O), -C(=O)NR7a-, and -NR7e-.

[0138] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is C1-4 alkyl, substituted with at least one =0 and one or more independently selected R3a, and R3ais -YA-LA-R5, wherein YA is absent and LA is -NR7e- or -NR7cC(=O)-.

[0139] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is CN.

[0140] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is halo. In a particular embodiment, one or more independently selected R3is selected from F, and Cl.

[0141] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein YA is absent.

[0142] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein YA is C1-4 alkylene optionally substituted with one or more independently selected halo. In a more particular embodiment, YA is -CH2-, or -CH2CH2-, each of which is optionally substituted with one or more independently selected halo.

[0143] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein YA is 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo. In a particular embodiment, YA is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted with one or more independently selected halo. In a more particular embodiment, YA is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally substituted with one or more F.

[0144] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein LA is absent.

[0145] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein LAis -O-, -C(=O)-, -C(=O)O-, -S(=O)-, or -S(=O)2-.

[0146] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein YA- is absent, and LA is -O-, -C(=O)-, -C(=O)O-, -S(=O)-, or -S(=O)2-.

[0147] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein LAis -C(=O)NR7a-, -C(=O)NR7a-C(=O)-,-S(=O)2NR7b-, -NR7fS(=O)2-, -NR7cC(=O)-, -P(=O)R7d-, or-NR7e-and each R7a, R7b, R7c, R7d, and R7eis as described for Formula I. In a particular embodiment, each R7a, R7b, R7C, R7d, R7eand R7fis independently selected from H, C1-4 alkyl, and 3-7 membered monocyclic cycloalkyl. In a more particular embodiment, each R7a, R7b, R7c, R7d, and R7eis independently selected from H, -CH3, -CH2CH3, and cyclopropyl.

[0148] In a most particular embodiment, LA is -C(=O)NH-, -S(=O)2NH-, -NHS(=O)2-, -NHC(=O)-, -P(=O)CH3-, or -NH-. In another most particular embodiment, LA is -C(=O)NCH3-, -S(=O)2NCH3-, -N(CH3)S(=O)2-, -NCH3C(=O)-, -P(=O)CH3-, or -NCH3-. In yet another most particular embodiment, LA is -C(=O)NcPr-, -S(=O)2NcPr-, - NcPrS(=O)2-, -NcPrC(=O)-, or -NcPr-.

[0149] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein LAis -C(=O)NR7a-, -S(=O)2NR7b-, -NR7cC(=O)-, -P(=O)R7d-, or -NR7e- and each R7a, R7b, R7c, R7d, and R7eis as described for Formula I. in a particular embodiment, each R7a, R7b, R7c, R7d, and R7eis independently selected from H, C1.4 alkyl, and 3-7 membered monocyclic cycloalkyl. In a more particular embodiment, each R7a, R7b, R7c, R7d, and R7eis independently selected from H, -CH3, -CH2CH3, and cyclopropyl. In a most particular embodiment, LA is -C(=O)NH-, -S(=O)2NH-, -NHC(=O)-, -P(=O)CH3-, or -NH-. In another most particular embodiment, LA is -C(=O)NCH3-, -S(=O)2NCH3-, -NCH3C(=O)-, -P(=O)CH3-, or -NCH3-. In yet another most particular embodiment, LA is -C(=O)NcPr-, -S(=O)2NcPr-, -NcPrC(=O)-, or -NcPr-.

[0150] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein YA- is absent, and LAis -C(=O)NR7a-, -S(=O)2NR7b-, -NR7fS(=O)2-, -NR7cC(=O)-, -P(=O)R7d-, or -NR7e-and each R7a, R7b, R7c, R7d, and R7eis as described for Formula I. in a particular embodiment, each R7a, R7b, R7c, R7d, R7eand R7fis independently selected from H, C1-4 alkyl, and 3-7 membered monocyclic cycloalkyl. In a more particular embodiment, each R7a, R7b, R7c, R7d, and R7eis independently selected from H, -CH3, -CH2CH3, and cyclopropyl. In a most particular embodiment, LA is -C(=O)NH-, -S(=O)2NH-, -NHS(=O)2-, -NHC(=O)-, -P(=O)CH3-, or -NH-. In another most particular embodiment, LA is -C(=O)NCH3-, -S(=O)2NCH3-, - N(CH3)S(=O)2-, -NCH3C(=O)-, -P(=O)CH3-, or -NCH3-. In yet another most particular embodiment, LA is -C(=O)NcPr-, -S(=O)2NcPr-, - NcPrS(=O)2-, -NcPrC(=O)-, or -NcPr-.

[0151] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein YA- is absent, and LAis -C(=O)NR7a-, -S(=O)2NR7b-, -NR7cC(=O)-, -P(=O)R7d-, or -NR7e- and each R7a, R7b, R7C, R7d, and R7eis as described for Formula I. in a particular embodiment, each R7a, R7b, R7c, R7d, and R7eis independently selected from H, C1-4 alkyl, and 3-7 membered monocyclic cycloalkyl. In a more particular embodiment, each R7a, R7b, R7c, R7d, and R7eis independently selected from H, -CH3, -CH2CH3, and cyclopropyl. In a most particular embodiment, LA is -C(=O)NH-, -S(=O)2NH-, -NHC(=O)-, -P(=O)CH3-, or -NH-. In another most particular embodiment, LA is -C(=O)NCH3-, -S(=O)2NCH3-, -NCH3C(=0)-, -P(=0)CH3-, or -NCH3-. In yet another most particular embodiment, LA is -C(=O)NcPr-, -S(=O)2NcPr-, -NcPrC(=O)-, or -NcPr-.

[0152] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is -YA-LA-R5, wherein YA- is absent or C1-4 alkylene, and LA is selected from the group comprising -NH-C(=O)-, -NCH3-C(=O)-, -C(=O)-, -C(=O)-NH-, -C(=O)-NCH3-, -NCH3-, -O-, -S(=O)2-, -C(=O)-O-, -S(=O)2-NH-, -NH-S(=O)2-, -NH-, and -NcPr-.

[0153] The following embodiments are applicable to any one of formulae I-IVb.

[0154] In one embodiment, In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as previously described, and one or more independently selected R3is selected from R5, -CH2-R5, -C(=O)OR5, -C(=O)NHR5, -CH2-C(=O)NHR5, -NHC(=O)R5, -C(=O)R5, -S(=O)2NHR5, -NHS(=O)2R5, -S(=O)2R5, -NHR5, -OR5, -NH-CH2-R5, or -P(=O)CH3R5.

[0155] In one embodiment, R5is H.

[0156] In one embodiment, R5is C1-4 alkyl. In a particular embodiment, R5is -CH3, or -CH2CH3.

[0157] In one embodiment, R5is C1-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl. In a particular embodiment, R5is -CH3, or -CH2CH3, each of which is optionally substituted with one or more independently selected halo, OH, phenyl or pyridinyl.

[0158] In one embodiment, R5is C1.4 alkyl substituted with one or more independently selected halo, OH, phenyl or pyridinyl. In a particular embodiment, R5is -CH3, or -CH2CH3, each of which is substituted with one or more independently selected halo, OH, phenyl or pyridinyl. In a more particular embodiment, R5is -CF3, -CHF2, -CH2-phenyl, or -CH2-pyridinyl.

[0159] In one embodiment, R5is 3-7 membered monocyclic cycloalkyl. In a particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In a particular embodiment, R5is cyclopropyl.

[0160] In one embodiment, R5is 3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In one embodiment, R5is 3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is cyclopropyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is optionally substituted with one ormore independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0161] In one embodiment, R5is 3-7 membered monocyclic cycloalkyl substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is cyclopropyl substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each of which is substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0162] In one embodiment, R5is 3-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In one embodiment, R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R5is aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl.

[0163] In one embodiment, R5is 3-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, -S(=O)2-cyclopropyl, -C(=O)OCH3, -S(=O)2CH3, -C(=0)-cyclopropyl, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In one embodiment, R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, or thiomorpholinyl, each of which is optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, morpholinyl, or thiomorpholinyl, each of which is optionally substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0164] In one embodiment, R5is 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more independently selected halo,OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1.4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, or thiomorpholinyl, each of which is substituted with one or more independently selected F, Cl, -OH, =0, phenyl, pyridinyl, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0165] In one embodiment, R5is 6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms.

[0166] In one embodiment, R5is 6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is 6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms optionally substituted with one or more independently selected F, Cl, -OH, =0, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3. In one embodiment, R5is 2-oxa-5-azabicyclo[2.2.1]heptanyl, diazepanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, 3,9-diazaspiro[5.5]undecanyl, 2-azaspiro[3.3]heptanyl, 2,8-diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, or 2-oxaspiro[3.3]heptanyl, optionally substituted with one or more independently selected F, Cl, -OH, =0, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0167] In one embodiment, R5is 6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is 6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one or more independently selected F, Cl, -OH, =0, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0168] In one embodiment, R5is phenyl.

[0169] In one embodiment, R5is phenyl substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, CI-4 alkyl optionally substituted with one or more independently selected halo, or C1.4 alkoxy optionally substituted with one or more independently selected halo. In a particular embodiment, R5is phenyl substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -0CH3, -OCF3, -C(=0)NH2, or -C(=0)NHCH3.

[0170] In one embodiment, R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl.

[0171] In one embodiment, R5is 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo.

[0172] In a particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, or pyrazolopyrimidinyl, each of which is optionally substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, C1-4alkyl optionally substituted with one or more independently selected halo, or C1-4alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl, pyridazinyl, thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, or pyrazolopyrimidinyl, each of which is optionally substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0173] In a particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected halo, OH, -C(=O)NH2, -C(=O)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo. In a more particular embodiment, R5is pyrazolyl, oxazolyl, thiaoxazolyl, furanyl, thienyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is substituted with one or more independently selected F, Cl, -OH, -CH3, -CHF2, -CF3, -OCH3, -OCF3, -C(=O)NH2, or -C(=O)NHCH3.

[0174] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is CN.

[0175] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from -CH3, -CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2-C(=O)NH2, -CH2-C(=O)NHCH3, -CH2-S(=O)2NH2, -CH2-NH-S(=O)2CH3, -CH2-phenyl, -CH2-C(=O)-morpholino, and -CH2-pyridinyl.

[0176] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0177] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[0178] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from -OH, -OCH3, -OCH2CH3, -OCH2CH(CH3)2, -OCH2-phenyl, -OCH2-pyridinyl, and -O-cyclopropyl.

[0179] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from -NH2, -NHCH3, -N(CH3)2, -NH-cyclopropyl, and -NHCH2-phenyl.

[0180] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from the group comprising -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH2CH3)CH3, -C(=O)N(CH3)2, -C(=O)NH-pyridinyl, -C(=O)imidazolyl, -C(=O)-pyrazolyl, -

[0181] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected fromO, -NH(C=O)pyridinyl, and O, wherein * represents the attachment point.

[0182] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from* / N^X-S(=O)2NH2, -S(=O)2NHCH3, andL— J, wherein * represents the attachment point.

[0183] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from ■I-S(=O)2CH3, -S(=O)2CH2CH3, and wherein * represents the attachment point.

[0184] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from -NHS(=O)2CH3and -NHS(=O)2CH2CH3.

[0185] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from -C(=NH)NH2.

[0186] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from -P(=O)(CH3)2.

[0187] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is as described for Formula I, and one or more independently selected R3is selected from the

[0188] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is selected from the group comprising:phenyl substituted with one, two or three independently selected R3;pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, and pyrazolopyrimidinyl, each of which is optionally substituted with one, two or three independently selected R3, where the N heteroatoms may optionally be oxidized;cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, and bicyclo[2.2.2]octanyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R3;azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, and azaphosphinanyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R3;2-oxa-5-azabicyclo[2.2.1]heptanyl, diazepanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro- 1H-furo[3,4-c]pyrrolyl, 3,9-diazaspiro[5.5]undecanyl, 2-azaspiro[3.3]heptanyl, 2,8- diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridinyl, and 2-oxaspiro[3.3]heptanyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R3; andCi-4 alkyl substituted with one, two or three groups independently selected from =0 and R3a.

[0189] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:

[0190] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:, wherein * represents the points of attachment.

[0191] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:, wherein * represents the points of attachment.

[0192] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:or, wherein * represents the points of attachment.

[0193] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:attachment.

[0194] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:, wherein * represents the points of attachment.

[0195] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:*, or *, wherein * represents the points of attachment.

[0196] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:O

[0197] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:

[0198] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:represents the points of attachment.

[0199] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:, wherein * represents the points of attachment.

[0200] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:*. or V, wherein * represents the points of attachment.

[0201] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:, wherein * represents the points of attachment.

[0202] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:wherein * represents the points of attachment.

[0203] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:

[0204] In one embodiment, the compound of the invention is according to any one of Formula I-IVb, wherein R1is:

[0205] In one embodiment, the compound of the invention is selected from the compounds of Table II herein.

[0206] In one embodiment, a compound of the invention are provided in a natural isotopic form.

[0207] In one embodiment, a compound of the invention are provided in an unnatural variant isotopic form. In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (i.e.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0208] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0209] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.

[0210] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0211] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

[0212] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0213] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.

[0214] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.

[0215] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0216] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

[0217] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which havemetabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0218] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgard, H, 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly useful are the C1to C8alkyl, C2-C8alkenyl, aryl, C7-C12substituted aryl, and C7-C12arylalkyl esters of the compounds of the invention.PHARMACEUTICAL COMPOSITIONS

[0219] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0220] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0221] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0222] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms mayinclude, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.

[0223] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0224] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0225] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0226] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17thedition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0227] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences.

[0228] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.Formulation 1 - Tablets

[0229] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.Formulation 2 - Capsules

[0230] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The mixture may be filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0231] A compound ofthe invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U. S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.Formulation 4 - Tablets

[0232] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.Formulation 5 - Injection

[0233] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.Formulation 6 - Topical

[0234] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75°C and then a mixture of A compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.METHODS OF TREATMENT

[0235] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM).

[0236] In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in the manufacture of a medicament for use in the prophylaxis and / or treatment of tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM).

[0237] In additional method of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM),which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition.

[0238] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, and another therapeutic agent. In a particular embodiment, the other therapeutic agent is a tuberculosis (TB) and / or non-tuberculous mycobacteria (NTM)treatment agent.

[0239] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 1 g / day for a 40 to 80 kg human patient.

[0240] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens. In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0241] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.

[0242] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0243] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0244] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0245] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0246] In one embodiment, a compound of the invention is co-administered with the standard of care for Mycobacterium avium complex (MAC) infections, namely azithromycin or clarithromycin, along withethambutol and rifampin. In a specific embodiment, a compound of the invention could be in the place of rifampin along with azithromycin or clarithromycin, and ethambutol.

[0247] In one embodiment, a compound of the invention is co-administered with the standards of care for Mycobacterium tuberculosis including isoniazid (CAS#54-85-3), pyrazinamide (CAS#98-96-4), and ethambutol (CAS#74-55-5).

[0248] In one embodiment, a compound of the invention is co-administered with one or more compound from one or more compounds from the following classes of compounds;Macrolide antibiotic such as but not limited to azithromycin (CAS#83905-01-5) or clarithromycin (CAS#81103-11-9),aminoglycoside antibiotic such as but not limited to gentamicin (CAS# 1403-66-3), tobramycin (CAS#32986-56-4), amikacin (CAS#37517-28-5), plazomicin (CAS#1154757-24-0), streptomycin (CAS#57-92-1), neomycin (CAS# 1404-04-2) and paromomycin (CAS# 1263-89-4),carbapenem antibiotics such as but not limited to imipenem (CAS#64221-86-9), meropenem (CAS#119478-56-7),Fluoroquinolones such as but not limited to levofloxacin (CAS#100986-85-4), ciprofloxacin (CAS#85721-33-1), moxifloxacin (CAS#151096-09-2), ofloxacin (CAS#82419-36-1), gemifloxacin (CAS#175463-14-6) and delafloxacin (CAS#189279-58-1),Oxazolidinones such as but not limited to linezolid (CAS#165800-03-3), posizolid (CAS#252260-02- 9), tedizolid (CAS#856866-72-3) and radezolid (CAS#869884-78-6),Tetracyclines such as but not limited to tetracycline (CAS#60-54-8), doxycycline (CAS#564-25-0), minocycline (CAS# 10118-90-8), tigecycline (CAS#220620-09-7),Cephalosporins such as but not limited to cefazolin (CAS#25953-19-9), cephalexin (CAS#25953-19- 9), cefuroxime (CAS#55268-75-2), cefoxitin (CAS#35607-66-0), ceftriaxone (CAS#73384-59-5), ceftazidime (CAS#72558-82-8), cefepime (CAS#88040-23-7), ceftaroline (CAS#229016-73-3), Riminophenazine antimycobacterials such as but not limited to clofazimine (CAS#2030-63-9), and bedaquiline (CAS#843663-66-1).

[0249] In a further embodiment a compound of the invention is used in combination with one or more inhibitor(s) of the mycobacterial enzymes InhA, Dprel, coenzyme A, adenosine triphosphate (ATP) synthase.

[0250] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i.e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.CHEMICAL SYNTHETIC PROCEDURESGeneral

[0251] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred processconditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0252] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Greene, T W; Wuts, P G M;, 1991).

[0253] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0254] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified.

[0255] Key analytical characterization was carried out by means of 1H-NMR spectroscopy and / or mass spectrometry (MS, m / z for [M+H]+ and / or [M-H]-) for all the exemplary compounds and selected intermediate products.LC-MS Methods

[0256] LC-MS analyses of the final compounds were performed on a Waters system combining: a Acquity UPLC H-Class equipped with a Acquity UPLC PDA Detector (range 190-420 nm), a Acquity UPLC ELS Detector and a Acquity TQ Detector (ESI / ESCi).

[0257] LC-MS Method A (BEH - Neutral 20%)

[0258] Column: UPLC BEH Premier C18 (2.1x50mm, 1.7pm) thermostated at 40°C; Mobile phase A: 5 mM aqueous solution of ammonium acetate (adjusted to pH 7 with aq. ammonia) + 5% acetonitrile; Mobile phase B: acetonitrile; Gradient (Time / % of B) 0 / 16, 3.18 / 58, 4 / 90, 5 / 90; Flow rate 0.5 mL / min; UV detection: from 190 nm to 420 nm; MS conditions: Ionisation Mode: Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1000 m / z, ES+ / -.

[0259] LC-MS Method B (BEH - Neutral 50%)

[0260] Column: UPLC BEH Premier C18 (2.1x50mm, 1.7pm) thermostated at 40°C; Mobile phase A: 5 mM aqueous solution of ammonium acetate (adjusted to pH 7 with aq. ammonia) + 5% acetonitrile; Mobile phase B: acetonitrile; Gradient (Time / % of B) 0 / 48, 3.5 / 90, 5 / 90; Flow rate 0.5 mL / min; UV detection: from 190 nm to 420 nm; MS conditions: Ionisation Mode: Positive and Negative Electrospray Ionisation (ESI+ / ESI-); Scan Range: 100 to 1000 m / z, ES+ / -

[0261] LC-MS analyses of Cpd 059 & Cpd 060 were performed on a Shimadzu LCMS-2020 equipped with a SPD-M40 PDA detector.

[0262] LC-MS Method C (C18 - Neutral)

[0263] Column: Shim-pack Scepter C18-120 (3.0x33 mm, 3.0 pm) thermostated at 40 °C; Mobile phase A: 5 mM aqueous solution of ammonium acetate + 5% acetonitrile; Mobile phase B: acetonitrile; Gradient (Time / % of B) 0 / 5, 1.20 / 90, 1.80 / 90; Flow rate 1.5 mL / min; UV detection: from 190 nm to 400 nm; MS conditions: Ionisation Mode: Positive Electrospray Ionisation (ESI+); Scan Range: 90 to 2000 m / z, ES+.Table I. List of abbreviations used in the experimental sectionAbbreviation Definition Abbreviation Definition ACN acetonitrile DMF N, N -dimethylformamide AcOH acetic acid DMSO dimethylsulfoxide aq. aqueous 1, 1 '-bis(diphenylphosphino) ATP dppf ferrocene adenosine 5 '-triphosphate(CAS# 12150-46-8) b.i.d. bis in die (twice a day)eq. or equiv. equivalent Boc tert-butyloxy-carbonylEt2O diethyl ether br s broad singletEtOAc ethyl acetate calcd calculatedEtOH ethanol chemical abstracts serviceCAS# h hourregistry number1, 1 '-carbonyldiimidazole 1 -[bis(dimethylamino)methyl CDI(CAS# 530-62-1) ene] - 1H- 1,2,3 -triazolo [4,5 -b] 1, 1 '-carbonyl -di-( 1,2,4- HATE pyridinium 3-oxid hexafluoro CDTtriazole) (CAS# 41864-22-6) phosphate (CAS# 148893-10-1) cPr cyclopropyl1 -Hydroxybenzotriazole (7, 7-dimethyl-2 -oxobicyclo HOBtCAS# 123333-53-9[2.2.1 ]heptan- 1 -yl)methaneCSA high-performance liquid sulfonic acid; Camphorsul HPLCchromatography fonic acid CAS# 5872-08-2i-PrOH isopropanol d doubletliquid chromatography-mass DCE dichloroethane LC-MSspectrometry DCM dichloromethanem multiplet dd doublet of doubletsm / z mass-to-charge ratio N, N -diisopropylethylamineDIPEA MeOH methanol (CAS# 7087-68-5)min minute4-DimethylaminopyridineDMAP(CAS# 1122-58-3) MTBE methyl tert-butyl etherAbbreviation DefinitionMW molecular weight NA not available obsd observedPBS phosphate-buffered saline p.o. per os (orally) ppm part-per-million q.d. quaque die (once daily) RT room temperature r.t. retention time s singletsat. saturatedt tripletTEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuranSYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTIONExample 1. General synthetic routes

[0264] The compounds presented herein may be prepared inter alia, via the general methods presented below.1.1. Reaction scheme 1

[0265] The C16-C17 and C18-C19 double bonds of Rifabutin CAS# 72559-06-9 can be reduced by catalytic hydrogenation using hydrogen gas. Both obtained epimers at C16 carbon can be separated by column chromatography. From both separated C16-epimers, the free hydroxyl groups (at C21 and C23) are then protected, typically as an acetonide. Ester hydrolysis of the acetate at C25, is followed by formation of an activated species (carbamate) which can then react with a selected amine derivative (primary or secondary) to form the carbamate. Further groups manipulations can be performed at this stage. The synthetic route is concluded by removal of the protecting groups.1.2. Reaction scheme 2

[0266] The free hydroxyl groups (at C21 and C23) of Rifabutin CAS# 72559-06-9 are protected, typically as an acetonide. Ester hydrolysis of the acetate at C25, is followed by formation of an activated species (carbamate) which can then react with a selected amine derivative (primary or secondary) to form the carbamate. The protecting groups (at C21 and C23) are then removed. The synthetic route is concluded by the reduction of the C16-C17 and C18-C19 double bonds by catalytic hydrogenation using hydrogen gas.

[0267] The C16-C17 and C18-C19 double bonds of Rifabutin CAS# 72559-06-9 can be reduced by catalytic hydrogenation using hydrogen gas. Both obtained epimers at C16 carbon can be separated by column chromatography. From both separated C16-epimers, the free hydroxyl groups (at C21 and C23) are then protected, typically as an acetonide. Ester hydrolysis of the acetate at C25, is followed by protection of the nucleophilic atoms (typically with bis-Alloc protection). The new ester bond at position C25 is then installed via conventional methods (typically coupling with acid anhydride or with acid via activatingagent). Further groups manipulations can be performed at this stage. The synthetic route is concluded by removal of the protecting groups.1.4. Reaction scheme 4

[0268] The free hydroxyl groups (at C21 and C23) of Rifabutin are protected, typically as an acetonide, followed by ester hydrolysis of the acetate at C25. The new ester bond at position C25 is then installed via conventional methods (typically coupling with acid anhydride or with acid via an activating agent), and the acetonide protecting group is removed. The synthetic pathway is concluded by catalytic reduction of the C16-C17 and C18-19 double bonds, and separating the two epimers.1.5. Illustrative intermediates1.5.1. Int 1

[0269] To a stirred solution of Rifabutin CAS# 72559-06-9 (1 g, 1.18 mmol, 1.0 eq.) in MeOH (20 mL) at RT were added 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (500 mg) and the reaction mixture was then stirred at RT under hydrogen (30 psi) in a Parr shaker for 2 hours. After completion of the reaction, the reaction mixture was filtered through a celite bed, which was washed with THF (25 mL) and 10% MeOH in DCM (25 mL). The filtrate was dried over Na2SO4 and concentrated under reduced pressure. The crude residue which was purified by column chromatography over silica gel using a gradient of MeOH (0-2%) in DCM to yield 190 mg of Int 1 (first eluting)

[0270] LC-MS: m / z (calcd): 850.5; m / z (obsd): 851.4 (M+H)+

[0271] ’H NMR (CDCI3, 400 MHz) 5 = 14.84 (s, 1H), 9.46 (br s, 1H), 8.03 (s, 1H) 6.13 (d, 1 H), 5.10-5.06 (m, 1H), 4.89 (d, 1H), 3.84 (d, 1H), 3.60 (s, 1 H), 3.44-3.36 (m, 2H), 3.06 (s, 3H), 2.97-2.94 (m, 3H), 2.58-2.53 (m, 3H), 2.30 (s, 3H), 2.28 (d, 2H), 2.15-2.13 (m, 1H), 2.03 (s, 4H), 1.95-1.67 (m, 9H), 1.64 (m, 1H), 1.54-1.52 (br s, 2H), 1.41-1.28 (m, 8H), 1.00 (d, 3H), 0.93 (d, 6H), 0.74 (d, 3H), 0.49 (d, 3H), 0.10 (d, 3H).

[0272] and 160 mg of Int 2 (second eluting)

[0273] LC-MS: m / z (calcd): 850.5; m / z (obsd): 851.4 (M+H)+

[0274] ’H NMR (CDCI3, 400 MHz) 5 = 15.10 (s, 1H), 9.18 (br s, 1H), 8.43 (s, 1H) 6.21 (d, 1 H), 4.88-4.82 (m, 1H), 4.42 (d, 1H), 4.13 (m, 1H), 3.52 (s, 1 H), 3.38-3.35 (m, 2H), 3.26-3.24 (m, 1H), 3.07 (s, 3H), 2.95-2.88 (m, 3H), 2.67-2.53 (m, 3H), 2.33 (s, 3H), 2.29 (d, 2H), 2.04 (s, 1H), 2.02-1.98 (m, 6H), 1.85-1.78 (m, 4H), 1.75 (s, 3H), 1.69-1.64 (m, 2H), 1.41-1.36 (m, 4H), 1.27-1.12 (m, 4H), 0.99 (d, 3H), 0.94 (d, 6H), 0.77 (d, 3H), 0.54 (d, 3H), 0.05 (d, 3H).1.5.2. Int 1

[0275] To a stirred solution of Rifabutin CAS# 72559-06-9 (1.0 g, 1.18 mmol, 1.0 eq.) in MeOH (40 mL) at RT were added 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (1.0 g) and cinchonidine CAS# 485-71-2 (208 mg, 0.71 mmol, 0.6 eq.) and the reaction mixture was then stirred at RT under hydrogen (30 psi) in a Parr shaker. After completion of the reaction, the reaction mixture was filtered through a celite bed, which was washed with THF (40 mL) and 10% MeOH in DCM (40 mL). The filtrate was dried over Na2SO4 and concentrated under reduced pressure. The crude residue which was purified by column chromatography over silica gel using a gradient of MeOH (0-2%) in DCM to yield 200 mg of Int 1 (first eluting). LC-MS: m / z (calcd): 850.5; m / z (obsd): 851.4 (M+H)+

[0276] and 450 mg of Int 2 (second eluting). LC-MS: m / z (calcd): 850.5; m / z (obsd): 851.4 (M+H)1.5.3. Int 3

[0277] To a stirred solution of Int 2 (11.0 g, 12.9 mmol, 1.0 eq.) in DMF (110 mL) were added 2,2-dimethoxypropane (33.3 mL, 271.4 mmol, 21.0 eq.) and CSA (3.60 g, 15.5 mmol, 1.2 eq.) and the resulting reaction mixture was stirred at RT. After completion of the reaction, the reaction mixture was poured into ice cold water (300 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with a sat. aq. NaHCO₃ solution (500 mL), brine (250 mL), then dried over Na2SC>4 and concentrated under reduced pressure and thoroughly dried to yield 11.1 g of Int 3, which was used as such in the next steps.

[0278] LC-MS: m / z (calcd): 890.5; m / z (obsd): 892.5 (M+H)+1.5.4. Int 4

[0279] Int 4 was synthetized from Int 1, using a process analogous to that of Int 31.5.5. Int 5

[0280] To a stirred mixture of Int 3 (19.0 g, 21.32 mmol, 1.0 eq.) in MeOH (1330 mL) and water (570 mL) were added ZnCl₂ (7.25 g, 53.3 mmol, 2.5 eq.) and solid NaOH (17.05 g, 426.4 mmol, 20.0 eq.) at RT. The resulting reaction mixture was then stirred at 50 °C. After completion of the reaction, the reaction mixture was diluted with water (300 mL), solids were filtered-off and the filtrate was extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (250 mL), dried over Na2SO4, concentrated under reduced pressure and thoroughly dried to afford 14.0 g of Int 5, which was used as such in the next steps.

[0281] LC-MS: m / z (calcd): 848.5; m / z (obsd): 849.9 (M+H)+

[0282] ’HNMR (CDC13, 400 MHz) 5 = 15.02 (s, 1H), 9.10 (m, 1H), 7.84 (s, 1H), 5.99 (d, 1H), 5.31 (m, 1H), 3.64 (m, 1H), 3.27-3.19 (m, 2H), 3.14 (s, 3H), 3.08 (m, 1H), 2.98 (m, 1H), 2.94-2.84 (m, 2H), 2.71-2.51 (m, 2H), 2.72-2.47 (m, 1H), 2.31-2.27 (m, 2H), 2.22 (s, 2H), 1.97 (m, 1H), 1.73-1.59 (m, 5H), 1.57-1.40 (m, 6H), 1.38-1.32 (m, 1H), 1.30 (m, 1H), 1.26 (m, 2H), 1.19 (d, 3H), 0.94 (d, 6H), 0.91-0.88 (m, 4H), 0.87 (d, 3H), 0.84 (s, 1H), 0.78 (s, 3H), 0.71 (d, 3H), 0.55 (d, 3H).1.5.6. Int 6

[0283] Int 6 was synthetized from Int 4, using a process analogous to that of Int 51.5.7. Int 7

[0284] To a stirred solution of Int 5 (3.0 g, 3.53 mmol, 1.0 eq.) in DCE (20 mL) was added batchwise l,l'-carbonyl-di-(l,2,4-triazole) CAS# 41864-22-6 (five times 1.16 g, addition every 24h; 35.33 mmol, 10.0 eq.). The resulting reaction mixture was then stirred at RT. After completion of the reaction, the reaction mixture was diluted with water (300 mL) and extracted with DCM (3 x 250 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SC>4, concentrated under reduced pressure and thoroughly dried to afford 2.5 g of Int 7, which was used as such in the next step.

[0285] LC-MS: m / z (calcd): 943.5; m / z (obsd): 944.4 (M+H)+

[0286] ’H NMR (CDC13, 400 MHz) 5 = 14.93 (s, 1H), 9.23 (s, 1H), 8.71 (s, 1H), 8.02 (s, 1H), 7.85 (s, 1H), 6.05-6.02 (d, 1H), 5.28-5.19 (m, 2H), 3.48-3.46 (d, 1H), 3.08-2.91 (m, 4H), 2.82 (s, 3H), 2.78-2.62 (m, 3H), 2.30-2.22 (m, 6H), 2.05-1.95 (m, 3H), 1.83-1.81 (m, 4H), 1.76 (s, 4H), 1.72-1.29 (m, 9H), 1.20-1.18 (d, 3H), 1.07 (s, 3H), 0.96-0.94 (m, 7H), 0.90-0.72 (m, 12H), 0.62-0.60 (d, 3H).1.5.8. Int 8

[0287] Int 8 was synthetized from Int 6, using a process analogous to that of Int 71.5.9. Int 9

[0288] A stirred solution of Int 7 (1.5 g, 1.77 mmol, 1 eq.) in DCE (15 mL) was treated with 1,1'-carbonyldiimidazole CAS# 530-62-1 (2.86 g, 17.67 mmol, 10 eq.) at RT and the resulting reaction mixture was then stirred at 50 °C. After completion of the reaction, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SC>4, evaporated under reduced pressure and thoroughly dried to yield 1.0 g of Int 9, which was used as such in the next step.

[0289] LC-MS: m / z (calcd): 942.5; m / z (obsd): 944.0 (M+H)+1.5.10. Int 10

[0290] Int 10 was synthetized from Int 8, using a process analogous to that of Int 91.5.11. Int 11

[0291] To a stirred solution of Int 5 (10.0 g, 11.8 mmol, 1.0 eq.) and DIEA (50.3 mL, 282.7 mmol, 24 eq.) in DCM (30 mL) was added 2-(prop-2-yn-l-yloxy)ethyl carbonochloridate CAS# 2937-50-0 (15.0 mL, 141.3 mmol, 12.0 eq.) at 0 °C and the mixture was then slowly allowed to reach RT. After completion of the reaction, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SO4 and concentrated under reduced pressure to afford 10 g of Int 11, which was used as such in the next step.

[0292] LC-MS: m / z (calcd): 1016.5; m / z (obsd): 1017.3 (M+H)+

[0293] ’HNMR (CDC13, 400 MHz) 5 = 8.05 (s, 1H), 6.10-5.95 (m, 3H), 5.52-5.28 (m, 6H), 4.82-4.81 (m, 3H), 3.82 (m, 1H), 3.20-3.12 (m, 6H), 2.95-2.84 (m, 7H), 2.48-2.42 (m, 2H), 2.38-2.32 (m, 2H), 2.30 (s,3H), 1.89-1.80 (m, 1H), 1.77 (s, 3H), 1.75-1.74 (m, 2H), 1.61-1.58 (m, 1H), 1.56-1.54 (m, 1H), 1.43-1.34 (m, 8H), 1.17-1.15 (d, 6H), 1.14-1.11 (m, 1H), 0.96-0.90 (m, 8H), 0.68 (d, 3H), 0.61 (d, 3H), 0.57 (s, 3H).

[0294] Int 12 was synthetized from Int 6, using a process analogous to that of Int 111.5.12. Int 13

[0295] To a stirred solution of Int 11 (1.8 g, 1.77 mmol, 1.0 eq.) in DCE (20 mL) was added CDI (2.88 g, 17.7 mmol, 10 eq.) at RT and the resulting reaction mixture was then stirred at 50 °C. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (2 x 500 mL). The combined organic layers were washed with brine (25 mL), dried over Na2SC>4 and concentrated under reduced pressure. The crude residue which was purified by column chromatography over silica gel using a gradient of EtOAc (40-70%) in hexane to yield 2.0 g of Int 13.

[0296] LC-MS: m / z (calcd): 1026.5; m / z (obsd): 1025.6 (M-H)1.5.13. Int 14Step i1.5.13.1. Step i

[0297] To a solution of nicotinic acid (3.0 g, 24.4 mmol, 1 eq.) in DCM (50 mL) were added tert-butylpiperazine-1 -carboxylate CAS# 57260-71-6 (5.45 g, 29.2 mmol, 1.2 eq.), l-(3-dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (7.01 g, 36.6 mmol, 1.5 eq.), 1 -hydroxybenzotriazole (4.94 g, 36.6 mmol, 1.5 eq.) and DIPEA (12.77 mL, 73.1 mmol, 3 eq.) and the reaction mixture was stirred at RT. After completion of the reaction, the reaction was quenched with water (100 mL) and the separated organic phase was dried over Na2SC>4 and concentrated to afford the crude compound. This crude compound was washed with Et2O (2 x 100 mL) and then dried under vacuum to yield 2.2 g of tert-butyl 4-nicotinoylpiperazine-1-carboxylate.

[0298] LC-MS: m / z (calcd): 291.2; m / z (obsd): 292.4 (M+H)+

[0299] ’H NMR (CDC13, 400 MHz) 5 = 8.69-8.66 (m, 2H), 7.75 (m, 1H), 7.39-7.26 (m, 1H), 3.75-3.44 (m, 8H), 1.47 (s, 9H)1.5.13.2. Step ii

[0300] A solution of tert-butyl 4-nicotinoylpiperazine-l -carboxylate (1.8 g, 6.2 mmol, 1 eq.) in DCM (20 mL), cooled to 0 °C, was treated dropwise with a 4N HC1 solution in dioxane (10 mL) and the reaction mixture was warmed to RT. After completion of the reaction, the reaction mixture was evaporated under vacuum, then washed with Et₂O (2 x 50 mL) to afford a pale-yellow solid. This crude was resuspended in DCM and water, the aqueous phase was basified to pH-10 with 50% NaOH solution and the aqueous layer was extracted with DCM (5 x 30 mL). Combined organic phases were dried over Na₂SO₄ and evaporated under vacuum to yield 550 mg of piperazin- l-yl(pyridin-3-yl) methanone Int 14, which was used as such in the next step.

[0301] LC-MS: m / z (calcd): 191.1; m / z (obsd): 192.1 (M+H)+1.5.14. Int 151.5.14.1. Step i

[0302] A stirred solution of l-(tert-butoxy carbonyl) piperidine-4-carboxylic acid CAS# 84358-13-4 (3 g, 13.1 mmol, 1 eq.) in DMF (10 mL) was treated with cyclopropylamine CAS# 765-30-0 (0.91 mL, 13.1 mmol, 1 eq.) and HATU (4.98 g, 13.1 mmol, 1 eq.) at RT. After reaction completion, the reaction was quenched with water (100 mL) and extracted with DCM (2 x 250 mL). The combined organic phases were dried over Na2SC>4 and evaporated under vacuum to afford a crude residue which was purified by column chromatography over silica gel using a gradient of MeOH (3-5%) in DCM to yield 2.8 g of tert-butyl 4-(cyclopropyl carbamoyl) piperidine-1-carboxylate.

[0303] LC-MS: m / z (calcd): 268.2; m / z (obsd): 269.2 (M+H)+1.5.14.2. Step ii

[0304] A solution of tert-butyl 4-(cyclopropyl carbamoyl) piperidine- 1 -carboxylate (2.8 g, 10.4 mmol, 1 eq.) in DCM (30 mL), cooled to 0 °C, was treated dropwise with a 4N HC1 solution in dioxane (15 mL) and the reaction mixture was warmed to RT. After completion of the reaction, the reaction mixture was evaporated under vacuum. The residue was then triturated with Et2O and pentane and the obtained solid was filtered and thoroughly dried to afford 2.1 g of A-cyclopropylpiperidine-4-carboxamide hydrochloride Int 15

[0305] LC-MS: m / z (calcd): 168.1; m / z (obsd): 168.9 (M+H)+

[0306] The following amides compounds were synthesized using a similar procedure to that of Int 15, by selection of reagents, solvents and purification methods known by the skilled in the art.Amine reagent in Step i Obtained intermediate Morpholine Int 23 Dimethylamine (2M in MeOH) Int 24Amine reagent in Step i Obtained intermediate 4-Aminotetrahydropyran CAS# 38041-19-9 Int 251.5.15. Int 271.5.15.1. Step i

[0307] To a stirred solution of (S)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid CAS# 88495-54-9 (5 g, 21.8 mmol, 1 eq.) in DCM (30 mL) and THF (10 mL) was added Et3N (9.20 mL, 65.4 mmol, 3 eq.) and l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (3.38 g, 21.81 mmol, 1 eq.) followed by HOBt (2.94 g, 21.81 mmol, 1 eq.) at 0 °C. The reaction mixture was allowed to reach RT, was treated with cyclopropylamine CAS# 765-30-0 (1.49 g, 21.2 mmol, 1.2 eq.) and then stirred at RT. After reaction completion, the reaction was quenched with a sat. aq. NaHCO₃ solution and extracted with DCM (2 x 150 mb). The combined organic phases were dried over Na2SO4 and evaporated under vacuum to afford a crude residue which was purified by column chromatography over silica gel using a gradient of EtOAc (30-40%) in PE to yield 3.1 g of tert-butyl (S)-3 -(cyclopropyl carbamoyl) piperidine-1-carboxylate.

[0308] LC-MS: m / z (calcd): 268.2; m / z (obsd): 269.2 (M+H)+1.5.15.2. Step ii

[0309] A solution of tert-butyl (S)-3-(cyclopropyl carbamoyl) piperidine- 1 -carboxylate (3.1 g, 11.9 mmol, 1 eq.) in DCM (30 mL), cooled to 0 °C, was treated dropwise with a 4N HC1 solution in dioxane (15 mb) and the reaction mixture was warmed to RT. After completion of the reaction, the reaction mixture was evaporated under vacuum. The residue was taken up in an aq. sat. NaHCO₃ solution (20 mL) and extracted with DCM (2 x 150 mL). The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure, then triturated with Et2O and pentane and the obtained solid was filtered and thoroughly dried to afford 1.4 g of (S)- / V-cyclopropylpiperidine-3-carboxamide Int 27.

[0310] LC-MS: m / z (calcd): 168.1; m / z (obsd): 169.1 (M+H)+

[0311] The following compounds were synthesized using a similar procedure to that of Int 27, by selection of reagents, solvents and purification methods known by the skilled in the art.Obtained Acid reagent in Step i Amine reagent in Step iintermediate cis-4-((tert-butoxycarbonyl) amino)Morpholinecyclohexane- 1 -carboxylic acid Int 36CAS# 110-91-8CAS# 53292-90-3trans-4-((tert-butoxy carbonyl)Morpholineamino)cyclohexane- 1 -carboxylic acid Int 63CAS# 110-91-8CAS# 53292-89-01.5.16. Int 161.5.16.1. Step i

[0312] A stirred solution of cyclopropane carboxylic acid CAS# 1759-53-1 (2.15 g, 25.0 mmol, 1 eq.) in DMF (10 mL), was treated with HATU (9.49 g, 25.0 mmol, 1 eq.) and DIPEA (13.33 mL, 74.9 mmol, 3 eq.) at 0°C and the reaction mixture was then stirred for 30 minutes at RT. After 30 minutes, the reaction mixture was treated with tert-butyl 4-aminopiperidine-1-carboxylate CAS# 87120-72-7 (5.0 g, 25.0 mmol, 1 eq.) at RT. After completion of the reaction, the reaction was quenched with ice cold water (100 mL) and extracted with EtOAc (2 x 250 mL). The combined organic phases were dried over Na2SC>4 and evaporated under vacuum to yield a crude residue, which was purified by column chromatography over silica gel using a gradient of MeOH (3-5%) in DCM to yield 4 g of tert-butyl 4-(cyclopropylcarbamoyl)piperidine-l-carboxylate.

[0313] ’H NMR (CDC13, 400 MHz) 5 = 5.50 (d, 1H), 4.04-3.80 (m, 3H), 2.87-2.80 (m, 2H), 1.93-1.89 (m, 2H), 1.45 (s, 9H), 1.32-1.26 (m, 3H), 0.98-0.94 (m, 2H), 0.75-0.70 (m, 2H)1.5.16.2. Step ii

[0314] A solution of tert-butyl 4-(cyclopropylcarbamoyl)piperidine-1-carboxylate (3.0 g, 11.2 mmol, 1 eq.) in 1,4-dioxane (20 mL), cooled to 0 °C, was treated with 37% w / w aq. HC1 solution (6.11 mL, 167.7 mmol, 15 eq.) and the reaction mixture was then stirred at RT. After completion of the reaction, the reaction mixture was evaporated under vacuum. The residue was then triturated with Et2O and pentane and the obtained solid was filtered and thoroughly dried to yield 1.5 g of N-(piperidin-4-yl)cyclopropanecarboxamide hydrochloride Int 16, which was used as such in the next step.

[0315] ¹H NMR (CDCl3, 400 MHz) 5 = 9.06 (s, 1H), 3.82-3.80 (m, 3H), 3.56 (s, 1H), 3.24-3.21 (m, 2 H), 2.93-2.70 (m, 2H), 1.68-1.56 (m, 3H), 0.66-0.62 (m, 4H).

[0316] The following amides compounds were synthesized using a similar procedure to that of Int 16, by selection of reagents, solvents and purification methods known by the skilled in the art.Amine reagent in Step i Obtained intermediatel-tert-Butoxycarbonyl-4-(methylamino)piperidineInt 26CAS# 147539-41-1trans-tert-Butyl (4-aminocyclohexyl)carbamateInt 34CAS# 177906-48-8cis-tert-Butyl (4-aminocyclohexyl)carbamateInt 35CAS# 247570-24-71.5.17. Int 171.5.17.1. Step i

[0317] To a stirred solution of tert-butylpiperazine-1-carboxylate CAS# 57260-71-6 (2.0 g, 10.7 mmol, 1 eq.) in DCM (20 mL) were added triethylamine (1.81 mL, 12.9 mmol, 1.2 eq.) and cyclopropanesulfonyl chloride CAS# 139631-62-2 (1.66 g, 11.8 mmol, 1.1 eq.) at RT. After completion of the reaction, the reaction was quenched with water (50 mL) and extracted with DCM (2 x 150 mL). The combined organic phases was dried over Na2SO4 and evaporated under vacuum to afford a crude residue which was purified by column chromatography over silica gel using a gradient of MeOH (3-5%) in DCM to yield 2.1 g of tertbutyl 4-(cyclopropylsulfonyl)piperazine-1-carboxylate.

[0318] LC-MS: m / z (calcd): 290.1; m / z (obsd): 234.9 (M+H-isobutene)+

[0319] ¹H NMR (CDCl3, 400 MHz) 5 = 3.53 (t, 4H), 3.24 (t, 4H), 2.26-2.04 (m, 1H), 1.47 (s, 9H), 1.21-1.05 (m, 2H), 1.02-0.97 (m, 2H)1.5.17.2. Step ii

[0320] A solution of tert-butyl 4-(cyclopropylsulfonyl) piperazine-1-carboxylate (2.0 g, 6.9 mmol, 1 eq.) in DCM (10 mL), cooled to 0 °C, was treated dropwise with a 4N HC1 solution in dioxane (10 mL) and the reaction mixture was warmed to RT. After completion of the reaction, the reaction mixture was evaporated under vacuum. The residue was then triturated with Et2O and pentane and the obtained solid was filtered and thoroughly dried to yield 1.5 g of l-(cyclopropylsulfonyl)piperazine hydrochloride Int 17, which was used as such in the next step.

[0321] LC-MS: m / z (calcd): 190.1; m / z (obsd): 191.1 (M+H-HC1)+

[0322] ’H NMR (CDCI3, 400 MHz) 5 = 9.50 (s, 2 H), 3.46-3.43 (m, 4H), 3.17-3.15 (m, 4H), 2.76-2.69 (m, 1H), 1.03-0.95 (m, 4H)1.5.18. Int 291.5.18.1. Step i

[0323] A stirred solution of tert-butylpiperazine-1-carboxylate CAS# 57260-71-6 (0.5 g, 2.69 mmol, 1 eq.) in THF (25 mL) was treated with triethylamine (1.12 mL, 8.05 mmol, 3 eq.) and then with a solution of pyrrolidine- 1 -sulfonyl chloride CAS# 1689-02-7 (546 mg, 3.22 mmol, 1.2 eq) in THF (5 mL) over a period of 10 minutes. The resulting solution was then stirred at RT. After completion of the reaction, the reactionwas quenched with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic phases was dried over Na2SC>4 and evaporated under vacuum to yield 0.5 g of tert-butyl 4-(pyrrolidin-1-ylsulfonyl)piperazine-1-carboxylate.

[0324] LC-MS: m / z (calcd): 319.1; m / z (obsd): 320.0 (M+H)+1.5.18.2. Step ii

[0325] To a solution of tert-butyl 4-(pyrrolidin-l-ylsulfonyl)piperazine-1-carboxylate (0.5 g, 2.69 mmol, 1 eq.) in DCM (30 mL) was added dropwise trifluoroacetic acid (1.53 g, 13.4 mmol, 5 eq) and the reaction mixture was stirred 6 h at RT. After completion of the reaction, the reaction mixture was evaporated under vacuum. The residue was then triturated with Et2O and the obtained solid was filtered and thoroughly dried to yield 350 mg of l-(pyrrolidin-l-ylsulfonyl)piperazine as TFA salt Int 29, which was used as such in the next step.

[0326] LC-MS: m / z (calcd): 219.1; m / z (obsd): 220.1 (M+H)+

[0327] The following compounds were synthesized using a similar procedure to that of Int 29, by selection of reagents, solvents and purification methods known by the skilled in the art.Obtained Amine reagent in Step i Sulfonyl reagent in Step iintermediate tert-butyl piperidin-4-ylcarbamate pyrrolidine- 1 -sulfonyl chlorideInt 30 CAS# 73874-95-0 CAS# 1689-02-7tert-Butyl (3aR,6aS)-hexahydropyrrolo[3,4- cyclopropanesulfonyl chloridec]pyrrole-2( lH)-carboxylate Int 31CAS# 139631-62-2CAS# 250275-15-1tert-butyl 4-aminopiperidine- 1 -carboxylate ethane sulfonyl chlorideInt 32 CAS# 87120-72-7 CAS# 594-44-5tert-butyl piperidin-4-ylcarbamate cyclopropanesulfonyl chlorideInt 33 CAS# 73874-95-0 CAS# 139631-62-2tert-Butyl 2-azaspiro[3,3]heptan-6-ylcarbamate cyclopropanesulfonyl chlorideInt 37 CAS# 1118786-85-8 CAS# 139631-62-2tert-butyl ((lr,4r)-4- methanesulfonyl chloride (aminomethyl)cyclohexyl)carbamate) Int 55CAS# 124-63-0CAS# 177583-27-6

[0328] The following compounds were synthesized using a similar procedure to that of Int 29, by selection of reagents, solvents and purification methods known by the skilled in the art. When a reagent was used as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,...) was used to ensure neutralization of the TFA or hydrochloride salt.Obtained Amine reagent in Step i Reagent in Step iintermediate 4-(tert-Butoxycarbonylamino)piperidine 4-Morpholinylcarbonyl ChlorideInt 83 CAS# 73874-95-0 CAS# 15159-40-7tert-Butyl azetidin-3-ylcarbamate hydrochloride Methyl chloroformateInt 84CAS# 217806-26-3 CAS# 79-22-1tert-Butyl azetidin-3-ylcarbamate hydrochloride 4-Morpholinylcarbonyl ChlorideInt 85CAS# 217806-26-3 CAS# 15159-40-71.5.19. Int 181.5.19.1. Step i

[0329] A stirred solution of cis-4-((tert-butoxycarbonyl) amino) cyclohexane- 1 -carboxylic acid CAS# 53292-90-3 (5.0 g, 20.5 mmol, 1 eq.) in acetonitrile (50 mL) was treated with HATU (8.60 g, 22.6 mmol, 1.1 eq), NH4CI (1.65 g, 30.8 mmol, 1.5 eq.) and triethylamine (8.6 mL, 61.6 mmol, 3 eq.) at RT. After completion of the reaction, the reaction mixture was quenched with ice cold water, the obtained solid was filtered, washed with acetonitrile (2 x 100 mL) and thoroughly dried to yield 3.5 g of tert-butyl (cis)-4-carbamoylcyclohexyl)carbamate.

[0330] ’H NMR (DMSO-de, 400 MHz) 5 = 7.10 (m, 1H), 6.68 (d, 2H), 3.42 (m, 1H), 2.14-2.07 (m, 1H), 1.79-1.74 (m, 2H), 1.60-1.53 (m, 2H), 1.46-1.41 (m, 4H), 1.40 (s, 9H).1.5.19.2. Step ii

[0331] A stirred solution of tert-butyl ((ls,4s)-4-carbamoylcyclohexyl)carbamate (500 mg, 2.06 mmol, 1 eq.) in DCM (5 mL), at 0°C, was treated with TFA (0.79 mL, 10.3 mmol, 5 eq.). The reaction mixture was slowly allowed to RT and stirred at that temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to 250 mg of cis-4-aminocyclohexane-l -carboxamide as TFA salt Int 18, which was used as such in the next step.

[0332] ¹H NMR (DMSO-d6, 400 MHz) 5 = 10.99 (m, 1H), 7.64 (m, 3H), 7.24 (m, 1H), 6.81 (m, 1H), 3.10 (d, 1H), 2.29 (d, 1H), 1.89-1.84 (m, 2H), 1.71-1.63 (m, 4 H), 1.60-1.53 (m, 2H), 1.57-1.47 (m, 2H)

[0333] The following compounds were synthesized using a similar procedure to that of Int 18, by selection of reagents, solvents and purification methods known by the skilled in the art.Obtained Acid reagent in Step i Amine reagent in Step iintermediate trans-4-((tert-butoxy carbonyl)(S)-tetrahydrofuran-3-amine amino)cyclohexane- 1 -carboxylic acid Int 41CAS# 104530-79-2CAS# 53292-89-0trans-4-((tert-butoxy carbonyl)4-Aminotetrahydropyran amino)cyclohexane- 1 -carboxylic acid Int 42CAS# 38041-19-9CAS# 53292-89-0trans-4-((tert-butoxy carbonyl)(R)-tetrahydrofuran-3-amine amino)cyclohexane- 1 -carboxylic acid Int 43CAS# 111769-26-7CAS# 53292-89-0trans-4-((tert-butoxy carbonyl) 3-oxa-8-azabicyclo [3.2.1]octaneInt 44amino)cyclohexane- 1 -carboxylic acid hydrochlorideCAS# 53292-89-0 CAS# 904316-92-3trans-4-((tert-butoxy carbonyl) thiomorpholine 1,1 -dioxide amino)cyclohexane- 1 -carboxylic acid hydrochloride Int 45 CAS# 53292-89-0 CAS# 59801-62-6trans-4-((tert-butoxy carbonyl)methyl amine amino)cyclohexane- 1 -carboxylic acid Int 46(2M solution in THF)CAS# 53292-89-0trans-3 -(boc-aminomethyl)morpholine cyclobutanecarboxylic acid Int 47CAS# 110-91-8CAS# 1638772-03-83-((tert-butoxy carbonyl) amino) benzoic acid 4-Aminotetrahydropyran CAS#Int 48 CAS# 111331-82-9 38041-19-9trans-4-((tert-butoxy carbonyl)amino)cyclohexane- 1 -carboxylic acid Int 17 Int 49 CAS# 53292-89-0(2-((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid Ammonium chloride Int 53CAS# 189153-10-4trans-4-((tert-butoxy carbonyl) (3aR,6aS)-rel-Hexahydro- 1H- amino)cyclohexane- 1 -carboxylic acid furo[3,4-c]pyrrole Int 54 CAS# 53292-89-0 CAS# 55129-05-02-(cis-4-((tert-Butoxycarbonyl)amino)cyclohexyl)acetic acid Ammonium chloride Int 61 CAS# 327156-95-6trans-4-((tert-butoxy carbonyl) (1R,4R)-2-Oxa-5-azabicyclo amino)cyclohexane- 1 -carboxylic acid [2.2.1]heptane Hydrochloride Int 62 CAS# 53292-89-0 CAS# 601515-79-1trans-4-((tert-butoxy carbonyl)2-oxa-6-azaspiro[3,4]octane amino)cyclohexane- 1 -carboxylic acid Int 66CAS# 220290-68-6CAS# 53292-89-0trans-4-((tert-butoxy carbonyl) (1S,4S)-2-Oxa-5-azabicyclo amino)cyclohexane- 1 -carboxylic acid [2.2.1]heptane hydrochloride Int 67 CAS# 53292-89-0 CAS# 31560-06-2trans-4-((tert-butoxy carbonyl)Methyl piperazine- 1 -carboxylate amino)cyclohexane- 1 -carboxylic acid Int 68CAS# 50606-31-0CAS# 53292-89-0cis-4-((tert-butoxycarbonyl) amino)4-Aminotetrahydropyrancyclohexane- 1 -carboxylic acid Int 73CAS# 38041-19-9CAS# 53292-90-32-(trans-4-((tert-Butoxycarbonyl)methyl amine hydrochloride amino)cyclohexyl)acetic acid Int 76CAS# 593-51-1CAS# 189153-10-42-(trans-4-((tert-Butoxycarbonyl)morpholine amino)cyclohexyl)acetic acid Int 77CAS# 110-91-8CAS# 189153-10-4trans-4-((tert-butoxy carbonyl) 8-Oxa-2 -azaspiro [4.5] decane amino)cyclohexane- 1 -carboxylic acid hydrochloride Int 78 CAS# 53292-89-0 CAS# 1408074-48-5(R)-1-(tert-Butoxycarbonyl)pyrrolidine-3- Dimethylammonium chlorideInt 86carboxylic acid (CAS# 72925-16-7) (CAS# 506-59-2)1.5.20. Int 191.5.20.1. Step i

[0334] A stirred solution of 2-chloroisonicotinic acid CAS# 6313-54-8 (2.0 g, 12.7 mmol, 1 eq.) and benzyl alcohol (1.65 g, 15.2 mmol, 1.2 eq.) in dry toluene (60 mL) was treated portionwise with NaH (as a 60% w / w dispersion in mineral oil) ( 1.27 g, 31.7 mmol, 2.5 eq.) and the mixture was allowed to stir at RT.18-Crown-6 ether CAS# 17455-13-9 (0.44 g, 1.65 mmol, 0.13 eq.) was added and the mixture was then heated to 120 °C. After completion of the reaction, the mixture was cooled down to RT and quenched with 1M aqueous HCl (50 mL). Hexane (200 ml) was added and the resulting mixture was stirred at 0 °C for 1 h, during which a light brown solid was obtained. This solid was filtered off, washed with hexane and thoroughly dried to obtained 1.2 g of 2-(benzyloxy)isonicotinic acid Int 19, which was used as such in the next step.

[0335] LC-MS: m / z (calcd): 229.1; m / z (obsd): 230.5 (M+H)+

[0336] ’H NMR (DMSO-de, 400 MHz) 5 = 13.68 (m, 1H), 8.34 (d, 1H), 7.46-7.44 (m, 2H), 7.41-7.30 (m, 4H), 7.25 (s, 1H), 5.39 (s, 2H).1.5.21. Int 201.5.21.1. Step i

[0337] A stirred solution of trans-4-((tert-butoxycarbonyl) amino)cyclohexane-l -carboxylic acid CAS# 53292-89-0 (1.0 g, 4.11 mmol, 1 eq.) in DMF (10 mL) was treated with HATU (2.34 g, 6.17 mmol, 1.5 eq.) and DIPEA (2.20 mL, 12.45 mmol, 3 eq.) at RT and stirred for 5 minutes. The reaction mixture was then treated with dimethylamine (2M solution in MeOH, 3.08 mL, 6.61 mmol, 1.5 eq.) and then stirred at 90°C until reaction completion. The reaction mixture was quenched with water, the obtained solid was filtered and thoroughly dried to yield 500 mg of tert-butyl ((lr,4r)-4-(dimethylcarbamoyl)cyclohexyl)carbamate.

[0338] LC-MS: m / z (calcd): 270.2; m / z (obsd): 271.2 (M+H)+1.5.21.2. Step ii

[0339] A stirred solution of tert-butyl ((lr,4r)-4-(dimethylcarbamoyl)cyclohexyl)carbamate (500 mg, 1.85 mmol, 1 eq.) in ethanol (5 mL), at 0°C, was treated with a 4N HC1 solution in dioxane (5 mL, 20 mmol). The reaction mixture was then allowed to RT and stirred at that temperature until reaction completion, the reaction mixture was concentrated under reduced pressure. The residue was triturated with diethyl ether and the obtained solid was filtered and thoroughly dried to yield 300 mg of (lr,4r)-4-amino-N, N-dimethylcyclohexane-1 -carboxamide hydrochloride Int 20, which was used as such in the next step.

[0340] LC-MS: m / z (calcd): 170.1; m / z (obsd): 171.1 (M+H-HC1)+1.5.22. Int 211.5.22.1. Step i

[0341] To a stirred solution of trans-4-((tert-butoxy carbonyl) amino)cyclohexane-l -carboxylic acid CAS# 53292-89-0 (2 g, 8.22 mmol, 1 eq.) in DCM (20 mL) was added DIPEA (2.87 mL, 16.44 mmol, 2 eq.) and HATU (3.13 g, 8.22 mmol, 1 eq.) at 0 °C. The reaction mixture was allowed to reach room temperature, was stirred for 10 min, then treated with cyclopropylamine CAS# 765-30-0 (0.469 g, 8.22 mmol, 1 eq.) and stirred at room temperature for 16 h. The reaction mixture was quenched with water and extracted with DCM (2 x 150 mL). Combined organic phases were dried over Na2SC>4 and evaporated to yield 2.5 g of tert-butyl (( 1 r,4r)-4-(cyclopropylcarbamoyl)cyclohexyl)carbamate.

[0342] LC-MS: m / z (calcd): 282.2; m / z (obsd): 283.2 (M+H)+

[0343] ¹H NMR (CDCl3, 400 MHz) 5 = 5.52 (s, 1 H), 4.42 (br s, 1 H), 3.45 (br s, 1 H), 2.69 (m, 1 H), 2.09 (d, 2 H), 1.95-1.88 (m, 3 H), 1.50 (d, 2 H), 1.43 (s, 9 H), 1.08 (m, 2 H), 0.75 (m, 2 H), 0.45 (m, 2 H).1.5.22.2. Step ii

[0344] A stirred solution of tert-butyl ((1r,4r)-4-(cyclopropylcarbamoyl)cyclohexyl)carbamate (1.2 g, 4.25 mmol, 1 eq.) in DCM (10 mL) was added a solution of 4N HC1 in dioxane (6 mL) at 0 °C and the reaction mixture stirred at room temperature. After reaction completion, the reaction mixture was concentrated. The residue was resuspended in DCM, washed with a sat. aq. NaHCO₃ solution. The aqueous layer was extracted with 10% MeOH in DCM. The combined organic layers were dried over Na2SC>4 and evaporated to yield 410 mg of (lr,4r)-4-amino-N-cyclopropylcyclohexane-l-carboxamide Int 21.

[0345] LC-MS: m / z (calcd): 182.1; m / z (obsd): 183.1 (M+H)+

[0346] The following compounds were synthesized using a similar procedure to that of Int 21, by selection of reagents, solvents and purification methods known by the skilled in the art.Obtained Acid reagent in Step i Amine reagent in Step iintermediate 4-((tert-butoxy carbonyl) amino) benzoic acid cyclopropylamineInt 40CAS# 66493-39-8 CAS# 765-30-01.5.23. Int 22

[0347] Int 22 was synthetized from Int 12, using a process analogous to that of Int 131.5.24. Int 28NH2NH20=S=0 0=S=0ii Step i Step iiBn iBn1.5.24.1. Step i

[0348] To a stirred solution sulfamoyl chloride (2.62 g, 22.69 mmol, 2.0 eq) in THF (10 mL) was added dropwise, over a period of 30 minutes, a solution of 1 -benzylpiperazine (2.0 g, 11.35 mmol, l. O eq.) in THF (10 mL) and the reaction mixture was then stirred for 4 h at RT. After completion of the reaction, the reaction was diluted with water (200 mL) and extracted with 10% MeOH in DCM (2 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4 and evaporated to yield 1.0 g of 4-benzylpiperazine-l -sulfonamide.

[0349] LC-MS: m / z (calcd): 255.1; m / z (obsd): 256.1 (M+H)+1.5.24.2. Step ii

[0350] To a stirred suspension of 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (150 mg) in MeOH (6 mL) and water (2 mL) was added a solution of 4-benzylpiperazine-l -sulfonamide (600 mg, 2.35 mmol, 1.0 eq) in MeOH (6 mL) and the reaction mixture was then stirred at RT under an hydrogen atmosphere (balloon pressure) for 8 h. After completion, the reaction mixture was fdtered and filtrate was concentrated under reduced pressure to yield 350 mg of piperazine- 1 -sulfonamide Int 28.

[0351] LC-MS: m / z (calcd): 165.1; m / z (obsd): 166.1 (M+H)+1.5.25. Int 381.5.25.1. Step i

[0352] To a stirred solution of tert-butyl 4-oxopiperidine-1-carboxylate CAS# 79099-07-3 (2.0 g, 10.04 mmol, 1.0 eq.) in acetonitrile (20 mL) were added cyclopropylamine CAS# 765-30-0 (1.72 g, 30.11 mmol, 3.0 eq.) and acetic acid (0.058 mL, 1.00 mmol, 0.1 eq.) at 0 °C. After 1 h was added sodium cyanoborohydride (0.757 g, 12.05 mmol, 1.2 eq.) at 0 °C and the resulting reaction mixture was stirred for 16 h at RT. After completion of the reaction, the reaction mixture was quenched with ice cold water (100 mL) and extracted with 10% MeOH in DCM (3 x 150 mL). The combined organic layers were washedwith water (20 mL), then brine (20 mL), dried over Na2SC>4and evaporated to yield 1.5 g of tert-butyl 4-(cyclopropylamino)piperidine-1-carboxylate which was used as such in the next step.

[0353] LC-MS: m / z (calcd): 240.1; m / z (obsd): 241.2 (M+H)+1.5.25.2. Step ii

[0354] A solution of tert-butyl 4-(cyclopropylamino)piperidine-1-carboxylate (1.4 g, 5.83 mmol, 1 eq.) in 15 mL of a 4 N HC1 solution in dioxane was stirred 16h at RT. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, the residue was washed with diethyl ether (2 x 20 mL) and the obtained solid was filtered and dried to yield 1.7 g of N-cyclopropylpiperidin-4-amine hydrochloride Int 38.

[0355] LC-MS: m / z (calcd): 140.1; m / z (obsd): 141.1 (M+H)+1.5.26. Int 39Step i Step iiHHCI 1.5.26.1. Step i

[0356] A stirred solution of trans-methyl 4-((tert-butoxycarbonyl)amino)cyclohexanecarboxylate CAS# 146307-51-9 (2 g, 7.77 mmol, 1 eq.) in DMF (20 mL) was treated with NaH (as a 60% w / w dispersion in mineral oil) (0.622 mg, 15.54 mmol, 2 eq.) at 0 °C. After 10 min was added dropwise neat iodomethane (1.45 mL, 23.32 mmol, 3 eq.) at 0 °C and the resulting reaction mixture was then stirred for 16 h at RT. After completion of the reaction, the reaction mixture was quenched with ice cold water (50 mL) and then extracted with DCM (2 x 150 mL). The combined organic layers were washed with water (150 mL), then with brine (150 mL) and then dried over Na2SC>4 and evaporated to yield 1.5 g of methyl (lr,4r)-4-((tert-butoxy carbonyl) (methyl)amino) cyclohexane- 1 -carboxylate which was used as such in the next step.

[0357] LC-MS: m / z (calcd): 271.2; m / z (obsd): 272.2 (M+H)+1.5.26.2. Step ii

[0358] A stirred solution of methyl (lr,4r)-4-((tert-butoxy carbonyl) (methyl)amino) cyclohexane- 1-carboxylate (1.5 g, 5.53 mmol, 1 eq.) in dioxane (10 mL), at RT, was treated with a 4 N HCI solution in dioxane (10 mL) and the resulting reaction mixture was then stirred for 16 h. After completion of the reaction, the reaction mixture was evaporated under reduced pressure. The residue was washed with diethyl ether and n-pentane and the obtained solid was filtered and dried to yield 1.0 g of methyl (lr,4r)-4-(methylamino) cyclohexane- 1 -carboxylate hydrochloride Int 39.¹H NMR (D2O, 400 MHz) 5 = 3.70 (s, 3 H), 3.09 (m, 1 H), 2.70 (s, 3 H), 2.47-2.41 (m, 1 H), 2.21-2.11 (m, 4 H), 1.55-1.41 (m, 4 H).1.5.27. Int 50Step i Step ii1.5.27.1. Step i

[0359] To a stirred solution of nicotinic acid CAS# 59-67-6 (2.0 g, 16.25 mmol, 1 eq.) in DMF (10 mL) at RT, were added HATU (12.35 g, 32.5 mmol, 2 eq.), tert-butyl (S)-3 -aminopiperidine- 1 -carboxylate CAS# 625471-18-3 (4.88 g, 24.4 mmol, 1.5 eq) and DIPEA (8.66 m, 48.7 mmol, 3 eq.). The resulting reaction mixture was then stirred at RT. After completion of the reaction, the reaction mixture was quenched with ice cold water (25 m ). Precipitated solid was filtered, washed with diethyl ether and thoroughly dried to yield 2.5 g of tert-butyl (. S)-3-(nicotinamido)pipcridinc-l -carboxylate.

[0360] LC-MS: m / z (calcd): 305.1; m / z (obsd): 306.1 (M+H)+1.5.27.2. Step ii

[0361] To a stirred solution of tert-butyl (. S)-3-(nicotinamido)pipcridinc-l -carboxylate (2 g, 6.55 mmol, 1 eq.) inDCM (10 mb) was added trifluoroacetic acid (1.50 mb, 19.65 mmol, 3 eq.) at 0 °C and the resulting reaction mixture was then stirred at RT for 16 h. After reaction completion, the reaction mixture was concentrated, the residue was triturated with diethyl ether (10 mb) and the obtained solid was filtered and thoroughly dried to yield 800 mg of (. S)-A-(pipcridin-3-yl)nicotinamidc as TFA salt Int 50.

[0362] 1H NMR (DMSO-d6, 400 MHz) 5 = 9.03 (d, 1H), 8.77-8.75 (m, 1H), 8.63 (d, 1H), 8.25 (d, 1H), 7.61-7.57 (m, 1H), 4.17-4.15 (m, 1H), 3.33 (d, 1H), 3.23-3.16 (m, 1H), 2.91-2.79 (m, 2H), 1.93-1.89 (m, 2H), 1.71-1.59 (m, 2H).

[0363] The following compounds were synthesized using a similar procedure to that of Int 50, by selection of reagents, solvents and purification methods known by the skilled in the art.Obtained Amine reagent in Step i Acid reagent in Step iintermediate tert-butyl ( / ? ) -3 -aminopiperidine- 1 -carboxylate nicotinic acidInt 51 CAS# 188111-79-7 CAS# 59-67-6tetrahydro-2H-pyran-4- 4-(tert-Butoxycarbonylamino)piperidinecarboxylic acid Int 79 CAS# 73874-95-0CAS# 5337-03-11.5.28. Int 52Step i1.5.28.1. Step i

[0364] To a stirred solution of pyridin-3-ol CAS# 109-00-2 (2 g, 21.03 mmol, 1 eq.) in THF (30 mb) were added sequentially tert-butyl 4-hydroxypiperidine-l -carboxylate CAS# 109384-19-2 (4.23 g, 21.03 mmol,1 eq.), triphenylphosphine (8.27 g, 31.55 mmol, 1.5 eq) and diethyl azodicarboxylate CAS# 1972-28-7 (6.38 g, 31.55 mmol, 1.5 eq) at 0 °C and the resulting mixture was then stirred at RT for 10 min then at 55 °C for 16 h. After reaction completion, the reaction mixture was diluted with water (50 mL), quenched with a sat. aq. NaHCO₃ solution (50 mL) and then extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated. The crude residue was purified by column chromatography over silica gel using a gradient of EtOAc (0-80%) in hexane to yield 3.0 g of tert-butyl 4-(pyridin-3-yloxy)piperidine-l -carboxylate.

[0365] LC-MS: m / z (calcd): 278.2; m / z (obsd): 279.2 (M+H)+1.5.28.2. Step ii

[0366] To a stirred solution of tert-butyl 4-(pyridin-3-yloxy)piperidine-l -carboxylate (600 mg, 2.15 mmol, 1.0 eq.) in DCM (10 mL) was added trifluoroacetic acid (3 mL) at 0 °C and the resulting mixture was then stirred at RT. After reaction completion the reaction mixture was concentrated, the residue was triturated with diethyl ether (20 mL) and the obtained solid was filtered and thoroughly dried to yield 300 mg of 3-(piperidin-4-yloxy)pyridine as TFA salt Int 52.

[0367] LC-MS: m / z (calcd): 178.1; m / z (obsd): 179.0 (M+H-TFA)+1.5.29. Int 561.5.29.1. Step i

[0368] To a stirred solution of lH-pyrazole-4-carboxylic acid CAS# 37718-11-9 (3.0 g, 26.77 mmol, 1.0 eq.) in DMF (30 mL) were added EDC. HC1 CAS# 25952-53-8 (6.22 g, 40.15 mmol, 1.5 eq.), HOBt (1.81 g, 13.38 mmol, 0.5 eq.) and DIPEA (7.40 mL, 40.15 mmol, 1.5 eq.) at 0 °C. The reaction mixture was then stirred for 30 minutes at RT and tert-butylpiperazine-1 -carboxylate CAS# 57260-71-6 (7.48 g, 40.15 mmol, 1.5 eq.) was then added and the reaction mixture was stirred at RT for 16 h. After reaction completion, the reaction mixture was quenched with ice cold water and the obtained precipitated solid was filtered and thoroughly dried to yield 4.0 g of tert-butyl 4-( I / / -pyrazolc-3 -carbonyl) piperazine- 1-carboxylate.

[0369] LC-MS: m / z (calcd): 280.1; m / z (obsd): 281.2 (M+H)+1.5.29.2. Step ii

[0370] A stirred solution of tert-butyl 4-( lH-pyrazole-4-carbonyl) piperazine- 1 -carboxylate (3.0 g, 10.70 mmol, 1 eq) and DIPEA (7.48 mL, 42.81 mmol, 4 eq) in DCM (50 mL), at 0 °C, was treated with allyl chloroformate CAS# 2937-50-0 (1.37 mL, 12.84 mmol, 1.2 eq.) and the reaction mixture was then stirred at RT for 16 h. After reaction completion, the reaction was quenched with ice-cold water (200 mL) and extracted with DCM (2 x 250 mL). The combined organic layers were washed were washed with brine,dried over anhydrous Na2SC>4 and concentrated. The crude residue was purified by column chromatography over silica gel using a gradient of EtOAc (30-40%) in petroleum ether to yield 3.0 g of tert-butyl 4-(l-((allyloxy)carbonyl)- 1 H-py razolc-4-carbony I ) piperazine- 1 -carboxylate

[0371] LC-MS: m / z (calcd): 364.2; m / z (obsd): 365.3 (M+H)+1.5.29.3. Step Hi

[0372] To a stirred solution of tert-butyl 4-( 1 -((allyloxy )carbonyl )- 1 H-pyrazole-4-carbonyl) piperazine- 1-carboxylate (500 mg, 1.37 mmol, 1.0 eq.) in DCM (5 mL) was added trifluoroacetic acid (1 mL) at 0 °C and the resulting mixture was then stirred at RT. After reaction completion, the reaction mixture was concentrated, the residue was triturated with diethyl ether and pentane and the obtained solid was filtered and thoroughly dried to yield 300 mg of allyl 3 -(4-chloro-414-piperazine-l -carbonyl)- IH-pyrazole-l-carboxylate as TFA salt Int 56.

[0373] LC-MS: m / z (calcd): 264.2; m / z (obsd): 265.2 (M+H-TFA)+

[0374] The following compounds were synthesized using a similar procedure to that of Int 56, by selection of reagents, solvents and purification methods known by the skilled in the art.Obtained Amine reagent in Step i Acid reagent in Step iintermediate tert-butylpiperazine- 1 -carboxylate lH-pyrazole-3-carboxylic acid CAS#Int 57 CAS# 57260-71-6 1621-91-6tert-butyl (S)-3 -aminopiperidine- 1- lH-pyrazole-3-carboxylic acid CAS#Int 74 carboxylate CAS# 625471-18-3 1621-91-6tert-butyl (S)-3 -aminopiperidine- 1- lH-pyrazole-4-carboxylic acid CAS#Int 75carboxylate CAS# 625471-18-3 37718-11-9

[0375] The following compounds were synthesized using a similar procedure to that of Int 56 for steps it and zzz, by selection of reagents, solvents and purification methods known by the skilled in the art.Obtained Reagent in Step iiintermediate tert-butyl (2-azaspiro[3.3]heptan-6-yl) carbamate CAS# 1118786-85-8 Int 58 tert-butyl ( lH-pyrazol-4-yl) carbamate CAS# 130106-42-2 Int 59 tert-butyl l,4,5,7-tetrahydro-6H-pyrazolo[3,4-c] pyridine-6-carboxylate CAS#Int 60871726-73-71.5.30. Int 64Boc-lnt 64 Boc-lnt 65 Step v1.5.30.1. Step i

[0376] To a stirred solution of ethyl 1 -methyl -4-oxocyclohexane-l -carboxylate CAS# 147905-77-9 (3.0 g, 16.28 mmol, 1 eq.) in 7N methanolic ammonia (50 mL) was added 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (3.0 g) and the reaction mixture was stirred under hydrogen atmosphere (30 psi) for 16 h. After completion of the reaction, the reaction mixture was filtered over a Celite pad and the bed was washed with methanol (100 mL). The filtrate was concentrated to yield 3.0 g of ethyl 4-amino-l-methylcyclohexane- 1 -carboxylate.

[0377] LC-MS: m / z (calcd): 185.1; m / z (obsd): 186.2 (M+H)+1.5.30.2. Step ii

[0378] To an ice-cold stirred solution of ethyl 4-amino-l -methylcyclohexane- 1 -carboxylate (3 g, 16.19 mmol, 1 eq.) in methanol (20 mL) was added EtsN (3.41 mL, 24.29 mmol, 1.5 eq.) followed by di-tert-butyl dicarbonate CAS# 24424-99-5 (5.44 mL, 16.19 mmol, 1 eq) and the reaction mixture was then warmed to RT and stirred for 16 h. After completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated to yield 2.5 g of ethyl 4-((tert-butoxycarbonyl)amino)- 1 -methylcyclohexane- 1 -carboxylate.

[0379] LC-MS: m / z (calcd): 285.2; m / z (obsd): 286.3 (M+H)+1.5.30.3. Step Hi

[0380] To an ice-cold stirred solution of ethyl 4-((tert-butoxycarbonyl)amino)-l -methylcyclohexane- 1-carboxylate (2.5 g, 8.76 mmol, 1 eq.) in a mix of THF (40 mL), MeOH (40 mL) and water (15 mL) was added Lithium hydroxide monohydrate (1.05 g, 43.80 mmol, 5 eq.) and the resulting reaction mixture was heated to 50 °C and stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and washed with diethyl ether (3 x 50 mL). Organic phases were discarded. The aqueous layer was acidified to pH 4 with 10% aq. citric acid and then extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield 1.5 g of 4-((tert-butoxycarbonyl)amino)-l -methylcyclohexane- 1 -carboxylic acid.

[0381] LC-MS: m / z (calcd): 257.2; m / z (obsd): 258.2 (M+H)+1.5.30.4. Step iv

[0382] To a stirred solution of 4-((tert-butoxycarbonyl)amino)-l -methylcyclohexane- 1 -carboxylic acid (1.5 g, 5.83 mmol, 1 eq.) in DMF (20 mb) were added '-mcthylmorpholinc (1.18 g, 11.66 mmol, 2 eq.), EDC. HC1 CAS# 25952-53-8 (3.35 g, 17.49 mmol, 3 eq.), followed by HOBt hydrate (0.788 g, 5.83 mmol, 1 eq.). After stirring for 15 min, NH4CI (0.935 g, 17.49 mmol, 3 eq.) was added and stirring was continued for 16 h. After completion of the reaction, the reaction was quenched with cold water (100 mL) and the obtained precipitated solid was filtered, washed with water (100 mL) and dried to get the crude product which was purified by Prep HPLC (Column: X-Bridge Prep Shield RP18 OBD (19x250mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 20, 2 / 20, 10 / 40, 14 / 40, 14.1 / 99, 21.98 / 99, 22 / 20, 25 / 20; Temperature: Ambient). The pure fractions was concentrated and lyophilized. The mixture was further purified by Chiral SFC (Column: Chiralpak IG PACKED (25x150mm, 5μm), % CO2: 60%, % Co solvent: 40% (100% Methanol), Total Flow: 80 mL / min, Back Pressure: 100 Bar, Temperature: 30.0 °C, Wavelength: 205 nm, Stack time: 12.0 mins / injection, Loadability: 116 mg / injection, Solubility: 12mL of 50% Methanol in DCM). The pure fractions were concentrated and lyophilized to yield 180 mg of Boc-Int 64 (first eluting)

[0383] LC-MS: m / z (calcd): 256.2; m / z (obsd): 201.2 (M+H-isobutene)+

[0384] ’H NMR (CDCI3, 400 MHz) 5 = 5.59 (br s, 1H), 5.40 (br s, 1H), 4.48 (br s, 1H), 3.48 (br s, 1H), 1.89-1.79 (m, 4H), 1.77-1.60 (m, 2H), 1.44 (s, 9H), 1.40-1.37 (m, 2H), 1.22 (s, 3H)

[0385] and 370 mg of Boc-Int 65 (second eluting)

[0386] LC-MS: m / z (calcd): 256.2; m / z (obsd): 257.2 (M+H)+

[0387] ’H NMR (CDCI3, 400 MHz) 5 = 5.58 (br s, 1H), 5.26 (br s, 1H), 4.38 (br s, 1H), 3.42 (br s, 1H), 2.09-2.05 (m, 2H), 1.90 (d, 2H), 1.43 (s, 9H), 1.36-1.23 (m, 4H), 1.18 (s, 3H)1.5.30.5. Step v

[0388] A stirred solution of Boc-Int 64 (400 mg, 1.56 mmol, 1 eq.) in DCM (30 mL) was treated with trifluoroacetic acid (534 mg, 4.68 mmol, 3 eq.) and then stirred for 6 h at RT. After completion of the reaction, the reaction mixture was concentrated, the obtained crude material was triturated with diethyl ether (50 mL) followed by pentane (50 mL). The obtained solid was then thoroughly dried to yield 310 mg of Int-64 as a TFA salt.

[0389] Int 65 was obtained from Boc-Int 65, following a similar procedure to that of Int 64 for step iv, by selection of reagents, solvents and purification methods known by the skilled in the art.Structure elucidation of Int 64 and Int 65 was performed by NOE NMR experiments.1.5.31. Int 691.5.31.1. Step i

[0390] To a stirred solution of 4-(methoxycarbonyl) bicyclo [2.2.1] heptane- 1 -carboxylic acid CAS# 15448-77-8 (1.00 g, 5.045 mmol, 1 eq.) in toluene (10 mb) were added diphenylphosphorylazide CAS# 26386-88-9 (1.39 g, 5.045 mmol, 1 eq.) followed by triethylamine (0.728 mb, 5.045 mmol, 1 eq.) and the resulting reaction mixture was heated to 110 °C for 16 h. The reaction mixture was cooled to RT, tert-butyl alcohol (0.55 mb, 5.045 mmol, 1 eq.) was added and heating was continued at 110 °C for 16 h. After reaction completion, the reaction mixture was quenched with ice-cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to yield 600 mg of methyl 4-((tert-butoxy carbonyl) amino) bicyclo [2.2.1] heptane- 1-carboxylate.

[0391] LC-MS: m / z (calcd): 269.2; m / z (obsd): 270.2 (M+H)+1.5.31.2. Step ii

[0392] A stirred solution of methyl 4-((tert-butoxy carbonyl) amino) bicyclo [2.2.1] heptane- 1 -carboxylate (600 mg, 2.23 mmol, 1 eq.) in DCM (10 mL) was treated with trifluoroacetic acid (0.852 mb, 11.14 mmol, 5 eq.) at 0°C and then stirred for 16 h at RT. After completion of the reaction, the reaction mixture was concentrated, the obtained crude material was triturated with diethyl ether. The obtained solid was then thoroughly dried to yield 700 mg of methyl 4-aminobicyclo [2.2.1] heptane- 1 -carboxylate as TFA salt Int 69.

[0393] LC-MS: m / z (calcd): 169.1; m / z (obsd): 169.2 (M-TFA)+1.5.32. Int 701.5.32.1. Step i

[0394] To a stirred solution of l,4-dioxa-8-azaspiro [4.5] decane CAS# 177-11-7 (500 mg, 3.49 mmol, 1.0 eq.) in acetonitrile (5 mL) were added (S)-3-bromo-2-methylpropan-l-ol CAS# (801 mg, 5.24 mmol, 1.5 eq) and K2CO3 (2.41 g, 17.46 mmol, 5.0 eq.) at RT and the resulting reaction mixture was then stirred at 80 °C for 16 h. After completion of the reaction, solids were filtered off and filtrate was concentrated to yield 1.2 g of (R)-2-methyl-3-(l,4-dioxa-8-azaspiro [4.5] decan-8-yl) propan-l-ol, which was used as such.

[0395] LC-MS: m / z (calcd): 215.1; m / z (obsd): 216.1 (M+H)+1.5.32.2. Step i

[0396] To a stirred solution of ( / ?)-2-mcthyl-3-(l.4-dioxa-8-azaspiro [4.5] decan-8-yl) propan-l-ol (650 mg, 3.02 mmol, 1.0 eq.) in THF (6 mL) was added 6 mL of a 10% aq H2SO4 at 0 °C and the reaction mixture was then stirred at 60 °C for 16 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL), pH of the aqueous layer adjusted to ~7 with a sat. aq. NaHC’CF solution and thenextracted with 10%MeOH in DCM (2x500 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated to yield 400 mg of ( / ?)-l-(3-hydroxy-2-methylpropyl)piperidin-4-one Int 70.

[0397] LC-MS: m / z (calcd): 171.1; m / z (obsd): 172.2 (M+H)+

[0398] The following compounds were synthesized using a similar procedure to that of Int 70 by selection of reagents, solvents and purification methods known by the skilled in the art.Obtained Reagent in Step iintermediate(R)-3-bromo-2-methylpropan-l-ol CAS# 93381-28-3 Int 711.5.33. Int 721.5.33.1. Step i

[0399] To a stirred solution of piperidin-4-one hydrochloride CAS# 41979-39-9 (1.0 g, 11.9 mmol, 1 eq.) in acetonitrile (20 mL) were added K2CO3 (5.26 g, 38.04 mmol, 1.6 eq.) and 2-bromoacetamide (2.30 g, 16.64 mmol, 0.7 eq.) at RT and the resulting reaction mixture was stirred for 16 h at RT. After completion of the reaction, the reaction mixture was quenched with ice cold water (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated under reduced pressure to yield 500 mg of 2-(4-oxopiperidin-l-yl) acetamide Int 72 which was used as such.

[0400] 1H NMR (DMSO-d6, 400 MHz) 5 = 7.36 (brs, 2H), 3.03 (s, 2H), 2.76 (t, 4H), 2.38 (t, 4H)1.5.34. Int 801.5.34.1. Step i

[0401] To an ice-cold stirred solution of tert-butyl 4-(4-nitro-lH-pyrazol-l-yl) piperidine- 1 -carboxylate CAS# 1201916-87-1 (1.0 g, 3.37 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (2 mL) and the resulting reaction mixture was stirred at RT for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude residue was washed with n-pentane (10 mL), then thoroughly dried to yield 800 mg of 4-(4-nitro-lH-pyrazol-l-yl)piperidine as TFA salt.

[0402] LC-MS: m / z (calcd): 196.1 (-TFA); m / z (obsd): 197.1 (M+H-TFA)+1.5.34.2. Step ii

[0403] To an ice-cold stirred solution of 4-(4-nitro-lH-pyrazol-l-yl)piperidine as TFA salt (1.0 g, 3.41 mmol, 1.0 eq) in DCM (10 mL) was added triethylamine (1.48 mL, 10.23 mmol, 3.0 eq.) followed by Mesyl chloride (0.317 mL, 4.09 mmol, 1.2 eq.) and the resulting reaction mixture was stirred at RT for 1 h. After reaction completion, the reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SC>4 and concentrated under reduced pressure. The crude residue was washed with n-pentane (10 mL), then thoroughly dried to yield 700 mg of l-(methyl sulfonyl)-4-(4-nitro-lH-pyrazol-l-yl) piperidine.

[0404] LC-MS: m / z (calcd): 274.1; m / z (obsd): 275.1 (M+H)+1.5.34.3. Step Hi

[0405] To a stirred solution of l-(methyl sulfonyl)-4-(4-nitro-lH-pyrazol-l-yl) piperidine (700 mg, 2.19 mmol, 1.0 eq.) in MeOH (6 mL) were added 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (300 mg), BOC2O (0.730 mL, 3.28 mmol, 1.5 eq.) followed by triethylamine (1.213 mL, 8.750 mmol, 4.0 eq.) and the resulting reaction mixture was then stirred at RT for 16 h under an hydrogen atmosphere (balloon). After completion of the reaction, the reaction mixture was filtered over celite bed, which was then washed with methanol (20 mL). The filtrate was concentrated under reduced pressure and the crude was purified by column chromatography over silica gel using a gradient of EtOAc (30-60%) in hexane to yield 400 mg of tert-butyl (l-(l-(methyl sulfonyl) piperidin-4-yl)-lH-pyrazol-4-yl) carbamate.

[0406] LC-MS: m / z (calcd): 344.2; m / z (obsd): 345.2 (M+H)+1.5.34.4. Step iv

[0407] To an ice-cold stirred solution of tert-butyl (1-(1 -(methyl sulfonyl) piperidin-4-yl)-lH-pyrazol-4-yl) carbamate (400 mg, 1.161 mmol, 1.0 eq.) in DCM (5 mL) was added TFA (0.5 mL) and the resulting reaction mixture was stirred at RT for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure and the crude residue was washed with n-pentane (10 mL), then thoroughly dried to yield 250 mg of l-(l-(methylsulfonyl)piperidin-4-yl)-lH-pyrazol-4-amine as TFA salt Int 80 which was used as such.

[0408] LC-MS: m / z (calcd): 244.1 (-TFA); m / z (obsd): 245.2 (M+H-TFA)+1.5.35. Int 811.5.35.1. Step i

[0409] To an ice-cold stirred solution of 2-hydroxy-5 -nitropyridine CAS# 5418-51-9 (2.0 g, 14.28 mmol, 1 eq.) in DMF (10 mL) were added potassium carbonate (3.95 g, 28.55 mmol, 2 eq.) and iodomethane (2.43 g, 17.13 mmol, 1.2 eq.) and the resulting reaction mixture was stirred at RT for 2h. After reaction completion, the reaction mixture was quenched ice-cold water (200 mL) and the precipitated solid was filtered, then thoroughly dried to yield 2.0 g of l-methyl-5-nitropyridin-2(lH)-one.

[0410] 1HNMR (CDC13, 400 MHz) 5 = 8.63 (d, 1H), 8.10 (m, 1H), 6.57 (d, 1H), 3.66 (s, 3H).1.5.35.2. Step ii

[0411] To a stirred solution of l-methyl-5-nitropyridin-2(lH)-one (1.0 g, 6.49 mmol, 1 eq.) in methanol (10 mL) was added 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (1.0 g) and the resulting reaction mixture was stirred under a hydrogen atmosphere (balloon pressure) for 16h. After reaction completion, the reaction mixture was filtered through Celite, the Celite bed was washed with methanol (50 mL). The filtrate was evaporated and thoroughly dried to yield 600 mg of 5-amino-l-methylpiperidin-2-one Int 81 which was used as such.

[0412] 1HNMR (CDCls, 400 MHz) 5 = 3.47-3.40 (m, 1H), 3.38-3.05 (m, 2H), 2.93 (s, 3H), 2.54-2.48 (m, 1H), 2.41-2.39 (m, 1H), 2.06-1.98 (m, 2H), 1.71-1.64 (m, 2H).1.5.36. Int 821.5.36.1. Step i

[0413] To an ice-cold stirred solution of tert-Butyl (trans-4-(hydroxymethyl)cyclohexyl)carbamate CAS# 239074-29-4 (10.0 g, 43.61 mmol, 1 eq.) in DCM (100 mL) and THF (30 mL) were added triethylamine (28.37 mL, 196.2 mmol, 4.5 eq.), DMAP (1.33 g, 10.90 mmol, 0.25 eq.) and p-toluene sulfonyl chloride (24.94 g, 130.82 mmol, 3 eq.) and stirring was continued at RT for 16 h. After completion reaction, the reaction mixture was quenched with ice-cold water (500 mL), extracted with DCM (2 x 500 mL). The combined organic layer was washed with brine (1000 mL), dried over Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using a gradient of EtOAc (30-80%) in hexane to yield 12.0 g of ((lr,4r)-4-((tert-butoxy carbonyl) amino)cyclohexyl)methyl 4-methylbenzenesulfonate.

[0414] LC-MS: m / z (calcd): 383.2; m / z (obsd): 384.2 (M+H)+1.5.36.2. Step ii

[0415] To a stirred solution of ((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl 4-methylbenzenesulfonate (8.0 g, 20.86 mmol, 1 eq.) in DMSO (80 mL) was added potassium thioacetate CAS# 10387-40-3 (2.86 g, 25.03 mmol, 1.2 eq.) at 0°C and the resulting reaction mixture stirred at RT for 16 h. After reaction completion, the reaction mixture was quenched with ice cold water (500 mL), extracted with DCM (2 X 500 mL). The combined organic layer was washed with brine (700 mL), dried over Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using a gradient of EtOAc (30-80%) in hexane to yield 5.8 g of S-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl) ethanethioate.

[0416] LC-MS: m / z (calcd): 287.2; m / z (obsd): 288.1 (M+H)+1.5.36.3. Step Hi

[0417] To a stirred solution of N-Chlorosuccinimide (6.96 g, 52.19 mmol, 3 eq.) in acetonitrile (15 mL) were added water (7 mL) and AcOH (5 mL) dropwise at 0 °C. After stirring for 15 min, the reaction mixture was treated with a solution of S-(((lr,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl)methyl) ethanethioate (5.0 g, 17.40 mmol, 1 eq.) in acetonitrile (10 mL) at 0 °C and stirring was then continued at RT for 4 h. After reaction completion, the volatiles were evaporated under reduced pressure and the obtained crude was then triturated with diethyl ether and n-pentane, then thoroughly dried to yield 4.0 g of tert-butyl ((lr,4r)-4-((chlorosulfonyl)methyl)cyclohexyl)carbamate.

[0418] LC-MS: m / z (calcd): 311.1; m / z (obsd): 256.0 (M+H-Boc fragment)

[0419] Steps i to Hi performed according to US2022 / 00982081.5.36.4. Step iv

[0420] To a stirred solution of tert-butyl ((lr,4r)-4-((chlorosulfonyl)methyl) cyclohexyl)carbamate (4.0 g, 12.83 mmol, 1 eq.) in THF (40 mL) was added 50% aqueous ammonium hydroxide solution (20 mL) at 0 °C and the resulting reaction mixture was stirred at RT for 1 h. After reaction completion, the reaction mixture was evaporated under reduced pressure and crude residue was thoroughly dried to yield 2.8 g of tert-butyl (( lr,4r)-4-(sulfamoyhnethyl)cyclohexyl)carbamate.

[0421] LC-MS: m / z (calcd): 292.1; m / z (obsd): 237.1 (M+H-Boc fragment)1.5.36.5. Step v

[0422] To an ice-cold stirred solution of tert-butyl ((lr,4r)-4-(sulfamoylmethyl)cyclohexyl)carbamate (2.8 g, 9.58 mmol, 1 eq.) in DCM (25 mL) was added dropwise trifluoroacetic acid (3.66 mL, 47.88 mmol, 5 eq.) and the reaction mixture was stirred at RT for 16 h. After reaction completion, the reaction mixture was evaporated under reduced pressure and the obtained crude was then triturated with diethyl ether and n-pentane to yield 3.0 g of ((lr,4r)-4-aminocyclohexyl)methanesulfonamide as a TFA salt Int 82 which was used as such.

[0423] LC-MS: m / z (calcd): 192.1; m / z (obsd): 193.1 (M+H)41.6. Illustrative compounds1.6.1. Cpd 0011.6.1.1. Step i (General procedure A - CDT mediated carbamate formation): Int A-Cpd 001

[0424] To a stirred solution of Int 7 (550 mg, 0.583 mmol, 1.0 eq.) in DCE (10 mL) was added tetrahydro-2H-pyran-4-amine CAS# 38041-19-9 (295 mg, 2.91 mmol, 5.0 eq.) and the reaction mixture was stirred at RT. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel using a gradient of MeOH (2-5%) in DCM to yield 200 mg of Int A-Cpd 001.

[0425] LC-MS: m / z (calcd): 975.6; m / z (obsd): 977.0 (M+H)+1.6.1.2. Step ii (General procedure D - CSA mediated acetonide deprotection): Cpd 001

[0426] To a stirred solution of Int A-Cpd 001 (180 mg, 0.184 mmol, 1.0 equiv) in MeOH (2 mL) was added CSA (86 mg, 0.37 mmol, 2.0 eq.) at 0°C and the reaction mixture was then stirred at RT. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with DCM (2x50 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by Prep HPLC (Column: XBridge C18 (19x150mm, 5μm); Mobile phase A: lOmM NH4HCO3 in water, Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 50,2 / 50,10 / 80,17.27 / 80,17.40 / 98,20.98 / 98,21 / 50,24 / 50; Temperature: Ambient). Pure fractions was concentrated and lyophilized to yield 40 mg of Cpd 001

[0427] LC-MS: m / z (calcd): 935.5; m / z (obsd): 936.8 (M+H)+

[0428] ’H NMR (CDCI3, 400 MHz) 5 = 14.98 (m, 1H), 8.57 (m, 1H), 8.64-8.49 (m, 1H), 6.23 (d, 1H), 4.77-4.63 (m, 2H), 4.22 (m, 1H) 4.05 (m, 1H), 3.97-3.94 (m, 1H), 3.72-3.22 (m, 10 H), 3.15-2.96 (m, 6H), 2.72-2.67 (m, 1H), 2.33 (s, 3H), 2.10-2.01 (m, 2H), 1.93-1.78 (m, 6H), 1.74 (s, 3H), 1.69 (m, 2H), 1.43 (m, 1H), 1.41 (m, 4H), 1.46-1.37 (m, 1H), 1.30-1.07 (m, 12H), 1.00 (d, 3H), 0.76 (d, 3H), 0.53 (m, 3H), 0.06 (m, 3H).1.6.2. Cpd 0221.6.2.1. Step i (General procedure B - MeOTf mediated carbamate formation): Int A-Cpd 022

[0429] To a solution of Int 9 (350 mg, 0.37 mmol, 1 eq.) in DCM (5 mL) was added methyl trifluoromethane sulfonate CAS# 333-27-7 (91 mg, 0.56 mmol, 1.5 eq.) at 0 °C and the resulting solution was then allowed to stir 15 min at RT. The reaction mixture was then evaporated under reduced pressure to afford 350 mg of the crude methylated imidazole intermediate, which was used as such in the next step.

[0430] To a stirred solution of crude methylated imidazole intermediate (300 mg, 0.31 mmol, 1.0 eq.) in DCM (10.0 mL) were added Int 18 (89 mg, 0.63 mmol, 2.0 eq.) and triethylamine (0.142 mL, 0.96 mmol, 3.0 eq.) at 0 °C and the reaction mixture was slowly allowed to reach RT and stirred until reaction completion. The reaction mixture was quenched with ice cold water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4 and concentrated under reduced pressure to yield 280 mg of Int A-Cpd 022, which was used as such in the next step.

[0431] LC-MS: m / z (calcd): 1016.6; m / z (obsd): 1017.8 (M+H)1.6.2.1. Step ii (General procedure E - HCl mediated acetonide deprotection): Cpd 022

[0432] To a stirred solution of Int A-Cpd 022 (260 mg, 0.256 mmol, 1.0 eq.) in THF (5 mL) was added IN aq. HCl (5.0 mL) at 0°C and the reaction mixture was then slowly allowed RT and stirred until reaction completion. The reaction mixture was then diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4 and concentrated under reduced pressure. The crude was purified by Prep HPLC (Column: YMC TRIART ACTUS C18 (20x150mm, 5μm); Mobile phase A: lOmM NH4HCO3 in water, Mobile phase B: Acetonitrile; Flow rate: 15 mL / min; Gradient: (Time / % OF B): 0 / 60, 2 / 60,10 / 80, 16.54 / 80,17 / 98, 24.74 / 98,25 / 60, 28 / 60; Temperature: Ambient). Pure fractions was concentrated and lyophilized to yield 45 mg of Cpd 022

[0433] LC-MS: m / z (calcd): 976.6; m / z (obsd): 977.8 (M+H)+

[0434] ’H NMR (CDCI3, 400 MHz) 5 = 15.16 (br s, 1H), 9.13 (br s, 1H), 8.47 (br s, 1H), 6.21 (d, 1H), 5.46 (m, 1H), 5.25 (m, 1H), 5.03 (m, 1H), 4.81 (m, 1H), 4.39 (m, 1H), 4.14 (m, 1H), 3.71 (s, 2H), 3.37 (m, 1H), 3.30-3.25 (m, 1H), 3.08 (s, 3H), 3.04-2.92 (m, 3H), 3.04-2.60 (m, 3H), 2.32 (s, 6H), 2.04-1.98 (m, 3H), 1.81-1.67 (m, 18H), 1.81-1.28 (m, 5H), 1.19 (d, 4H), 1.81-0.93 (m, 9H), 0.76 (d, 3H), 0.52 (d, 3H), 0.06 (d, 3H).

[0435] A solution of Int 9 (250 mg, 0.27 mmol, 1 eq.) in DCM (5 mL) was treated with methyl trifluoromethane sulfonate CAS# 333-27-7 (217 mg, 1.33 mmol, 5 eq.) at room temperature and then stirred 30 minutes at RT. The reaction mixture was then evaporated under reduced pressure to afford the crude methylated imidazole intermediate, which was used as such in the next step. LC-MS: m / z (calcd): 957.5; m / z MW (obsd): 956.5 (M-H) ).

[0436] To a stirred solution of the crude methylated imidazole intermediate (180 mg, 0.19 mmol, 1.0 eq.) in DCM (10 mL) was added Int 14 (182 mg, 0.95 mmol, 5.0 eq.) at RT. After reaction completion, the reaction mixture was quenched with water and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SC>4 and concentrated. The crude was purified by Prep HPLC (Column: XSelect CSH C18 (19x250mm, 5μm); Mobile phase A: lOmM NH4HCO3 in water, Mobile phase B: Acetonitrile; Flow rate: 18 mL / min; Gradient: (Time / % OF B): 0 / 50, 2 / 50, 10 / 85, 12 / 85, 12.1 / 98, 15 / 98, 15.1 / 50, 18 / 50; Temperature: Ambient). Pure fractions was concentrated and lyophilized to yield 20 mg of Cpd 035

[0437] LC-MS: m / z (calcd): 1025.6; m / z (obsd): 1026.7 (M+H)+

[0438] ’H NMR (CDCI3, 400 MHz) 5 = 14.88 (br s, 1H), 9.20-8.40 (m, 4H), 7.77-7.75 (m, 1H), 7.40-7.37 (m, 1H), 6.27 (d, 1H), 4.79-4.65 (m, 1H), 4.20 (s, 1H), 4.01-3.90 (m, 1H), 3.85-3.25 (m, 14H), 3.20-2.65 (m, 7H), 2.35-2.25 (m, 4H), 2.15-2.00 (m, 3H), 1.80-1.58 (m, 8H), 1.43-1.21 (m, 15H), 1.01-0.56 (m, 10H), 0.08- -0.10 (m, 3H).

[0439] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 035, by selection of reagents and purification methods known by the skilled in the art.Amine reagent Starting intermediate Final cpd Int 20 Int 9 Cpd 0362-methoxyaniline (CAS# 90-04-0) Int 10 Cpd 0371.6.4. Cpd 0381.6.4.1. Step i (General procedure C - BnBr mediated carbamate formation): Int A-Cpd 038

[0440] To a stirred solution of Int 9 (300 mg, 0.32 mmol, 1 eq) in acetonitrile (15 mL) was added benzyl bromide (0.113 mL, 0.95 mmol, 3 eq.) and the resulting reaction mixture was then stirred at RT until reaction completion. The reaction mixture was concentrated under reduced pressure, then triturated withdiethyl ether (2 x 10 mL). The obtained solid was filtered off and thoroughly dried to yield 300 mg of the crude benzylated imidazole intermediate which was used as such.

[0441] A stirred solution of trans-4-Aminocyclohexanecarboxamide CAS# 791775-31-0 (206 mg, 1.45 mmol, 5 eq.) in DCM (10 mL) was treated with triethylamine (146 mg, 1.45 mmol, 5 eq.) at 0 °C and then by the crude benzylated imidazole intermediate (300 mg, 0.29 mmol, 1.0 eq.) and the reaction mixture was then stirred at RT for 16h. After reaction completion, the reaction mixture was quenched with ice cold water (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-10%) in DCM to yield 270 mg of Int A-Cpd 038.

[0442] LC-MS: m / z (calcd): 1016.6; m / z (obsd): 1017.9 (M+H)1.6.4.2. Step ii: Cpd 038

[0443] To a stirred solution of Int A-Cpd 038 (260 mg, 0.256 mmol, 1.0 eq.) in THF (3 mL) was added a IN aq. HC1 solution (3.0 mL) at 0°C and the reaction mixture was then slowly allowed RT and stirred until reaction completion. The reaction mixture was then quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure. The crude was purified by Prep HPLC (Column: XSelect CSH C18 (19x150mm, 5μm); Mobile phase A: 0.1% formic acid in water, Mobile phase B: Acetonitrile; Flow rate: 13 mL / min; Gradient: (Time / % OF B): 0 / 75, 2 / 75, 10 / 95, 14 / 95, 14.1 / 99, 20.1 / 75, 25 / 75; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 21 mg of Cpd 038

[0444] LC-MS: m / z (calcd): 976.6; m / z (obsd): 977.9 (M+H)+

[0445] ’HNMR CDCh, 400 MHz) 5 = 15.15 (br s, 1H), 9.11 (br s, 1H), 8.48 (s, 1H), 7.55 (m, 1H), 6.22 (d, 1H), 5.41 (m, 1H), 5.30-5.24 (m, 1H), 4.83-4.77 (m, 1H), 4.59 (d, 1H), 4.34 (m, 1H), 4.13 (m, 1H), 3.70 (s, 1H), 3.44-3.35 (m, 2H), 3.26 (m, 1H), 3.07 (s, 3H), 3.01 (m, 1H), 2.96-2.90 (m, 2H), 2.71-2.55 (m, 3H), 2.33-2.27 (m, 5H), 2.10-1.98 (m, 8H), 1.87-1.80 (m, 3H), 1.75 (s, 3H), 1.68 (m, 2H), 1.54-1.50 (m, 2H), 1.42-1.33 (m, 4H), 1.29-1.25 (m, 3H), 1.19 (d, 3H), 1.11-1.06 (m, 2H), 1.00 (d, 3H), 0.93 (d, 6H), 0.76 (d, 3H), 0.51 (d, 3H), 0.08-0.05 (m, 4H).

[0446] The following carbamates compounds were synthesized using one of the above described procedures, by selection of amines reagents, solvents and purification methods known by the skilled in theart. When the starting amine reagent was prepared or used as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,... ) was used to ensure neutralization of the TFA or hydrochloride salt.Carbamate AcetonideStartingAmine reagent formation deprotection Final cpd intermediateprocedure procedure morpholine (CAS# 110-91-8) Int 8 A D Cpd 002 morpholine (CAS# 110-91-8) Int 7 A D Cpd 003 o _Hl / NHHCI Int 7 A D Cpd 004 Int 16piperazine (CAS# 110-85-0) Int 7 A D Cpd 005 cyclopropyl (piperazin- 1 -yl)methanoneInt 7 A D Cpd 006 (CAS# 59878-57-8)1 -cyclopropylpiperazine (CAS#Int 7 A D Cpd 007 59878-57-8)1 -Isobutylpiperazine (CAS# 5308-28- Int 7 A D Cpd 008 1)1 -Ethyl- 1,4-diazepane (CAS# 3619- Int 7 A D Cpd 009 73-6)3 -Ethyl-3, 9-diazaspiro [5.5 ]undecaneInt 7 A D Cpd 010 (CAS# 1260832-77-6)1 -cyclopropylpiperidin-4-amineInt 7 A D Cpd 011 (CAS# 396133-55-4)O A I I H Int 7 A DH2N*^X>Cpd 012 Int 218-oxa-2-azaspiro [4.5] decane (CAS#Int 7 A D Cpd 013 310-93-0)(lR,4R)-2-Oxa-5- azabicyclo[2.2. l]heptane Int 7 A D Cpd 014 hydrochloride (CAS# 601515-79-1)(lS,4S)-2-Oxa-5- azabicyclo[2.2. l]heptane Int 7 A D Cpd 015 hydrochloride (CAS# 31560-06-2)N, N-dimethylpiperidin-4-amineInt 7 A D Cpd 016 (CAS# 50533-97-6)I-cyclopropyl-N-methylpiperidin-4- Int 7 A D Cpd 017 amine (CAS# 1096334-18-7)AHCIk^NH Int 7 A D Cpd 062Int 23Carbamate Acetonide StartingAmine reagent formation deprotection Final cpd intermediateprocedure procedure9HCI' \ / NH Int 7 A D Cpd 063 Int 249 HCIHInt 7 A D Cpd 064 UHInt 252-Oxa-6-azaspiro[3,3]heptaneInt 7 A D Cpd 065 (CAS# 174-78-7)HN VN\ _ / \ Int 7 A D Cpd 066 HCIInt 26H_ N^O? HCIInt 7 A D Cpd 067 C^NHInt 27H2N / / °o'Ax-NHInt 7 A D Cpd 068 Int 28UJL '?Q' TFAInt 7 A D Cpd 069 A / NHInt 29GU°"S'N^° I 1^^NTHF2AInt 7 A D Cpd 070 Int 30cis-hexahydro-lH-furo[3,4-c]pyrroleInt 7 A D Cpd 071 (CAS# 55129-05-0)O / £^S-NNHInt 7 A D Cpd 072 HInt 31oHy' iTFA'° k^-NHInt 7 A D Cpd 073 Int 32HxyNyyhciV^NH Int 7 A D Cpd 074Int 38Carbamate Acetonide StartingAmine reagent formation deprotection Final cpd intermediateprocedure procedure / ^r-NH2o / '''A / VN-V TFAInt 7 A D Cpd 082 V 0Int 371 -ethyl- lH-pyrazol-4-amineInt 7 A D Cpd 091 (CAS# 876343-24-7)o i — \X / °Int 7 A D Cpd 092 Int 41O TFAInt 7 A D Cpd 093 ^l\FInt 50o 7~'~oTInt 7 A D Cpd 094 HFZAN^"^Int 42o i — \Int 7 A D Cpd 095 HzN*^^Int 43o. A HTFA HZN'^''^ 7?\ -O Int 7 A D Cpd 114HInt 54Octahydropyrrolo [3,4-c]pyrroleInt 7 A D Cpd 136 dihydrochloride (CAS# 165894-01-9)trans-4-Aminocyclohexanol (CAS#Int 7 A E Cpd 018 27489-62-9)l-(pyridin-3-yl) piperazine (CAS#Int 7 A E Cpd 019 67980-77-2)2,2,6,6-tetramethylpiperidin-4-amineInt 7 A E Cpd 020 (CAS# 36768-62-4)7-oxa-2-azaspiro[3.5]nonane (CAS#Int 7 A E Cpd 021 194157-10-3)(Y'C1Int 10 B D Cpd 023 Int 14Pyridin-3 -amine (CAS# 462-08-8) Int 10 B D Cpd 024Pyridin-3 -amine (CAS# 462-08-8) Int 9 B D Cpd 025Carbamate AcetonideStartingAmine reagent formation deprotection Final cpd intermediateprocedure procedure / \ 9 HCIHInt 10 B D Cpd 026 LJHInt 15 / \ 9 HCIHInt 9 B D Cpd 027 LJHInt 15Thiomorpholine 1,1 -dioxide (CAS#Int 9 B D Cpd 028 39093-93-1) / — \ °HN N-S — <3HCIX- / 6 Int 9 B D Cpd 029 Int 173 -amino-N -cyclopropylbenzamideInt 9 B D Cpd 030 (CAS# 871673-24-4)o Int 9 B D Cpd 075NH2Int 34ZSr"'QHCIInt 9 B D Cpd 076— ^NH2Int 35, —x0H2N— ( \ / N-S II^dInt 9 B D Cpd 077 TFA0Int 33A-cyclopropyltetrahydro-2H-pyran-4- Int 9 B D Cpd 078 amine (CAS# 211814-16-3)2-oxaspiro [3.3]heptan-6-amineInt 9 B D Cpd 080 (CAS# 1363381-78-5)oHCIInt 9 B D Cpd 081-A H2NInt 36oooHCI | | N 1Js. > k Int 9 B D Cpd 081-B H2N —Int 630< AN-\< YNH2Int 9 B D Cpd 096H TFAInt 48Carbamate Acetonide StartingAmine reagent formation deprotection Final cpd intermediateprocedure procedureO TFAInt 9 B D Cpd 097 NInt 51TFAInt 9 B D Cpd 098 Int 520.‘V\THF2\N^O Cv Int 9 B D Cpd 099 Int 49oTFAHZNA> Int 9 B D Cpd 100 Int 44o™ nAoH2N.*<X^-^ > < -S=O Int 9 B D Cpd 101 Int 45 \om / TFHfY m 'V Int 9 B D Cpd 102 H2N*^^Q- Isnt 46CN 11 < Z1 X- 0TFA P7’,'^NXX|Int 9 B D Cpd 103 H2N^< / ^'OInt 471, 5 -dimethyl- 1 H-pyrazol-3 -amineInt 9 B D Cpd 105 (CAS# 35100-92-6)TFA [ | TH2N*A^'^>° Int 9 B D Cpd 106 Int 53pyrazolo[l,5-a] pyrimidin-3 -amineInt 9 B D Cpd 107 (CAS# 232600-93-0)1, 3, 8-Triazaspiro[4.5]decane-2, 4-dioneInt 9 B D Cpd 108 (CAS# 13625-39-3)1, 8 -diazaspiro [4.5] decan-2-oneInt 9 B D Cpd 109 hydrochloride (CAS# 1389313-57-8)2,8-diazaspiro [4.5] decan-l-oneInt 9 B D Cpd 110 hydrochloride (CAS# 832710-65-3)Int 9 B D Cpd 115Carbamate Acetonide StartingAmine reagent formation deprotection Final cpd intermediateprocedure procedure7-oxa-2-azaspiro[3.5] nonaneInt 9 B D Cpd 121 (CAS# 194157-10-3)-ethyl-3 -methyl- lH-pyrazol-4-amineInt 9 B D Cpd 123 (CAS# 947763-34-0)oTFAInt 9 B D Cpd 126 Int 65TFA [ | TH2N’AX / >° Int 9 B D Cpd 127 Int 61oTFAInt 9 B D Cpd 128 H2N —Int 62oTFAj^J'' ^N HzInt 9 B D Cpd 130 H2NInt 640z\ ATFA j 1Int 9 B D Cpd 131 Int 660Int 9 B D Cpd 132 rl2NInt 671 -(tert-butyl)- lH-pyrazol-4-amineInt 9 B D Cpd 133 (CAS# 97421-13-1)0T„F2AN^M ^NY< KInt 9 B D Cpd 1340Int 680xTFA | |Int 9 B D Cpd 141 H2N A JInt 830Int 9 B D Cpd 142 H2N^^Int 73H TFA \ ] TInt 9 B D Cpd 143Int 76Carbamate AcetonideStartingAmine reagent formation deprotection Final cpd intermediateprocedure procedureoTFA / —N A O / H2N Int 9 B D Cpd 144 Int 84^'OTFA | ] T> O Int 9 B D Cpd 145 H2N —Int 77oTFAJO ' ^OCoInt 9 B D Cpd 154 Int 780tfaCNIAO Int 9 B D Cpd 155 Int 79TFA rN' OH2N > L N- ( y N-go a—Int 9 B D Cpd 156 Int 80methyl 4-aminopiperidine-l- Int 9 B D Cpd 157 carboxylate (CAS# 1019351-46-2)-N-yNH2Cpd 158, o^^ Int 9 B DCpd 159 Int 814-Aminocyclohexane- 1 -sulfonamide Cpd 169,Int 9 B D(CAS# 854443-96-2) Cpd 170.✓X^NH2H 2 Nd'T FAInt 9 B D Cpd 171 Int 82HN^ / - TFA L / Int 9 B D Cpd 176 Int 86Piperazin-2-one (CAS# 5625-67-2) Int 9 B D Cpd 1822-(Methylamino)acetamideInt 9 B D Cpd 184 hydrochloride (CAS# 5325-64-4)N-Methyl-1-(pyridin-3-yl)methanamine (CAS# 20173-04-0)1 -Methylpiperazin-2-oneInt 9 B D Cpd 192 (CAS# 59702-07-7)oTFA / " N A NH2N Int 9 B D Cpd 203 Int 852-Ethylpyrimidin-5 -amineInt 9 B D Cpd 206(CAS# 1152519-74-8)Carbamate AcetonideStartingAmine reagent formation deprotection Final cpd intermediateprocedure procedure2-aminoacetamide hydrochlorideInt 9 B D Cpd 207 (CAS# 1668-10-6)(. S')-Pyrrolidinc-2 -carboxamideInt 9 B D Cpd 208 hydrochloride (CAS# 42429-27-6)( / ?)-pyrrolidinc-2 -carboxamideInt 9 B D Cpd 209 (CAS# 62937-45-5)(. S')-2- Amino-3 -hydroxypropanamideInt 9 B D Cpd 210 hydrochloride (CAS# 65414-74-6)2-Amino-2-methylpropanamideInt 9 B D Cpd 211 (CAS# 16252-90-7)(S)-2 -amino-3 -methylbutanamideInt 9 B D Cpd 212 (CAS# 4540-60-7)2-amino- 1 -morpholinoethan- 1 -oneInt 9 B D Cpd 213 hydrochloride (CAS# 24152-96-3)-Pyridinemethanamine (CAS# 3731- Int 10 B E Cpd 031 52-0)-Pyridinemethanamine (CAS# 3731- Int 9 B E Cpd 032 52-0)2-methoxyaniline (CAS# 90-04-0) Int 9 B E Cpd 033 2-Amino-l,3,4-thiadiazole (CAS#Int 9 B E Cpd 034 4005-51-0)4-Aminotetrahydropyran (CAS#Int 10 C D Cpd 039 38041-19-9)cis-4-Aminocyclohexanol (CAS#Int 10 C E Cpd 040 40525-78-8)cis-4-Aminocyclohexanol (CAS#Int 9 C E Cpd 041 40525-78-8)trans-4- Aminocyclohexanecarboxamide Int 10 C E Cpd 042(CAS# 791775-31-0)Note: last step separation / purification of Cpd 158 and Cpd 159 was performed by Prep-SFC (Column: Chiralpak IK (30x250mm, 5μm), % CO2: 65%, % Co solvent: 35% (0.5% methanolic ammonia in methanol), Total Flow: 90 mL / min, Back Pressure: 100 Bar, Temperature: 30.0 °C, Wavelength: 277 nm, Stack time: 9.5 mins / injection, Loadability: 9.36 mg / injection).1.6.5. Cpd 0431.6.5.1. Step i: Int A-Cpd 043

[0447] To a stirred solution of Int 7 (700 mg, 0.74 mmol, 1.0 eq.) in DCE (10 mL) was added methyl (S)-piperidine-3 -carboxylate CAS# 276248-50-1 (531 mg, 3.71 mmol, 5.0 eq.) at RT and the reaction mixture was then stirred at 60 °C for 2 h. After reaction completion, the reaction mixture was concentrated and the crude residue was purified by column chromatography over silica gel using a gradient of EtOAc (0-70%) in PE to yield 600 mg of Int A-Cpd 043.

[0448] LC-MS: m / z (calcd): 1017.6; m / z (obsd): 1018.5 (M+H)+1.6.5.2. Step ii: Int B-Cpd 043

[0449] To a stirred solution of Int A-Cpd 043 (550 mg, 0.54 mmol, 1.0 eq.) in THF (6 mL) and water (6 mL) was added lithium hydroxide monohydrate (453 mg, 10.8 mmol, 20 eq.) at 0 °C and the resultingreaction mixture was then stirred for 2 h at RT. The reaction mixture was diluted with water (250 mL) and extracted with EtOAc (2x250 mL). The combined organic layers were washed with brine solution (400 mL), dried over Na2SC>4 and concentrated to yield Int B-Cpd 043 which was used as such in the next step.

[0450] LC-MS: m / z (calcd): 1003.6; m / z (obsd): 1004.4 (M+H)+1.6.5.3. Step Hi: Int C-Cpd 043

[0451] To a stirred solution of Int B-Cpd 043 (300 mg, 0.30 mmol, 1.0 eq.) in DMF (5 mL) were added HATU (170 mg, 0.45 mmol, 1.5 eq.), NH4CI (32 mg, 0.60 mmol, 2.0 eq.) and DIPEA (0.268 mL, 1.50 mmol, 5.0 eq.) at 0 °C temperature and the reaction mixture was then stirred for 1 h at RT. After completion of the reaction, the reaction mixture was quenched with water (200 mL) and extracted with DCM (2x 200 mL). The combined organic layers were washed with water (150 mL), brine (100 mL), dried over Na2SC>4 and concentrated to yield Int C-Cpd 043 which was used as such in the next step.

[0452] LC-MS: m / z (calcd): 1002.6; m / z (obsd): 1003.8 (M+H)+1.6.5.4. Step iv: Cpd 043

[0453] To a stirred solution of Int C-Cpd 043 (230 mg, 0.23 mmol, 1.0 eq.) in MeOH (5 mL) was added CSA (213 mg, 0.92 mmol, 4.0 eq.) at 0 °C and the reaction mixture was allowed to room temperature and stirred for 2 h. After reaction completion, reaction mixture was quenched with water (200 mL) and extracted with DCM (2x200 mL). The combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated. The crude was purified by Prep HPLC (Column: X-Select phenyl-hexyl (19x250mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B:Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 45, 2 / 45, 10 / 75, 15.68 / 75, 15.70 / 98, 21.98 / 98, 22 / 45, 25 / 45; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 45 mg of Cpd 043.

[0454] LC-MS: m / z (calcd): 962.5; m / z (obsd): 963.9 (M+H)+

[0455] 1H NMR (CDCl3, 400 MHz) 5 = 15.21 (br s, 1H), 9.18 (br s, 1H) 8.62-8.51 (m, 1H), 6.28 (m, 2H), 5.47 (m, 1H) 4.84-4.04 (m, 3H), 3.39-3.11 (m, 6H), 3.09-2.91 (m, 7H), 2.74-2.59 (m, 4H), 2.31-2.28 (m, 5H), 2.05-1.78 (m, 15H), 1.41-1.35 (m, 4H), 1.26 (m, 2H), 1.19 (d, 4H), 1.01 (m, 3H) 0.94 (m, 6H), 0.76 (d, 4H), 0.56 (s, 3H), 0.11 (d, 3H).

[0456] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 043, by selection of reagents, solvents and purification methods known by the skilled in the art. When the starting amine reagent was prepared as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,... ) was used to ensure neutralization of the TFA or hydrochloride salt.Amine reagent Starting intermediate Final cpd 4-Piperidinecarboxylic acid, methyl esterInt 7 Cpd 061 (CAS# 2971-79-1)methyl (3R)-piperidine-3-carboxylateInt 7 Cpd 079 (CAS# 164323-85-7)methyl ( 1 r, 3 r)-3 -aminocyclobutane- 1 -carboxylateInt 7 Cpd 111 hydrochloride (CAS# 74316-29-3)methyl ( 1 s,3 s)-3 -aminocyclobutane- 1 -carboxylateInt 7 Cpd 113hydrochloride (CAS# 1212304-86-3)1.6.6. Cpd 044

[0457] Cpd 044 was synthesized from Int B-Cpd 043 using a process analogous to that for Cpd 043 (step iv). Purification by Prep HPLC (Column: YMC TRIART ACTUS C18 (20x150mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 30, 2 / 30, 10 / 50, 14.98 / 50, 15 / 98, 19 / 98, 19.1 / 30,24 / 30; Temperature: Ambient). Pure fractions were concentrated to yield Cpd 044.

[0458] LC-MS: m / z (calcd): 963.5; m / z (obsd): 964.9 (M+H)+

[0459] ’H NMR (CDCI3, 400 MHz) 5 = 15.96 (br s, 1H), 12.30 (br s, 1H), 9.33-9.20 (m, 2H), 6.05 (d, 1H), 5.05-4.71 (m, 3H), 3.87-3.58 (m, 2H), 3.50-3.39 (m, 2H), 2.95-2.67 (m, 10H), 2.29-2.14 (m, 8H), 1.98-1.79 (m, 3H), 1.68-1.47 (m, 10H), 1.36-1.15 (m, 8H), 1.07 (m, 4H), 0.92-0.82 (m, 10H), 0.75 (m, 3H), 0.56-0.26 (m, 3H), 0.12 (m,2H).

[0460] To a stirred solution of Int 13 (1.6 g, 1.66 mmol, 1.0 eq.) in acetonitrile (20 mL) was added benzyl bromide (0.983 mL, 7.30 mmol, 5 eq.) at room temperature and the reaction was stirred for 16h. The reaction mixture was then concentrated under reduced pressure. The crude product was washed with 50 mL of Et20 and dried to yield the crude benzylated imidazole intermediate which was used as such.

[0461] A stirred solution of the crude benzylated imidazole intermediate (600 mg, 0.54 mmol, leq.) in DCE (30 mL) was treated with methyl 3 -aminobenzoate CAS# 4518-10-9 (243 mg, 1.61 mmol, 3 eq.) at room temperature and the resulting reaction mixture was then heated at 60 °C. After reaction completion, the reaction mixture was concentrated under reduced pressure and the crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-5%) in DCM to yield 250 mg of Int A-Cpd 045.

[0462] LC-MS: m / z (calcd): 1109.6; m / z (obsd): 1110.8 (M+H)+1.6.7.2. Step ii: Int B-Cpd 045

[0463] To a stirred solution of Int A-Cpd 045 (250 mg, 0.244 mmol, 1 eq.) in DCM (30 mL) were added tetrakis(triphenylphosphine)palladium CAS# 14221-01-3 (56.3 mg, 0.049 mmol, 0.2 eq.) and 1,3-dimethylbarbituric acid CAS# 769-42-6 (57 mg, 0.365 mmol, 1.5 eq.) at 0 °C and the reaction mixture was stirred for 10 min. After completion of the reaction, reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure, the crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-5%) in DCM to yield 240 mg of Int B-Cpd 045.

[0464] LC-MS: m / z (calcd): 1025.5; m / z MW (obsd): 1026.4 (M+H)+1.6.7.3. Step Hi: Int C-Cpd 045

[0465] To a stirred solution of Int B-Cpd 045 (240 mg, 0.234 mmol, 1 eq.) in THF (4 mL) and MeOH (4 mL), was added a solution of KOH (98 mg, 2.34 mmol, 10 eq.) in water (4 mL) at RT and the resulting reaction mixture was then heated at 55 °C and stirred for 1 h. After reaction completion, the reaction mixture was diluted with water (50 mL) and the pH of the aqueous layer was brought to pH=7 by addition of a 10% aq citric acid solution. The aqueous phase was extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine solution (100 mL), dried over Na2SC>4 and concentrated to yield 230 mg of Int C-Cpd 045.

[0466] LC-MS: m / z (calcd): 1011.5; m / z (obsd): 1012.3 (M+H)+1.6.7.4. Step iv: Int D-Cpd 045

[0467] To a stirred solution of Int C-Cpd 045 (220 mg, 0.22 mmol, 1 eq.) in DMF (20 mL) were added HATU (165 mg, 0.435 mmol, 2 eq.), NH4CI (58 mg, 1.09 mmol, 5 eq.) and DIPEA (0.234 mL, 1.30 mmol, 6 eq.) at 0 °C. The resulting reaction mixture was then allowed to room temperature and stirred for 1 h. After completion of the reaction, reaction mixture was quenched with water (50 mL) and extracted with DCM (2x 50 mL). The combined organic layers were washed with water and brine solution. The organic layer was dried over Na2SC>4 and concentrated to yield 200 mg of Int D-Cpd 045.

[0468] LC-MS: m / z (calcd): 1010.5; m / z (obsd): 1011.3 (M+H)+1.6.7.5. Step v: Cpd 045

[0469] To a stirred solution of Int D-Cpd 045 (200 mg, 0.198 mmol, 1 eq) in MeOH (20 mL) was added CSA (184 mg, 0.79 mmol, 4 eq.) at 0 °C and the reaction mixture was then allowed to reach room temperature and was stirred for 1 h. After completion of the reaction, reaction mixture was quenched with water (50 mL) and extracted with DCM (2x 50 mL). The combined organic layers were washed with water (50 mL) and brine solution (50 mL), dried over Na2SC>4 and concentrated. The crude was purified by Prep HPLC (Column: XSelect CSH C18 (19x150mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 17 mL / min; Gradient: (Time / % OF B): 0 / 70,2 / 70,10 / 90,12 / 90,12.1 / 98,15 / 98,15.1 / 70,22 / 70; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 27 mg of Cpd 045.

[0470] LC-MS: m / z (calcd): 970.5; m / z (obsd): 971.8 (M+H)+

[0471] ’HNMR (CDCh-d, 400 MHz) 5 = 15.19 (br s, 1H), 9.16 (br s, 1H), 8.50 (br s, 1H), 7.87 (s, 1H), 7.53 (m, 2H), 7.43-7.39 (m, 1H), 6.90 (m, 1H), 6.29-6.22 (m, 1H), 5.64-5.50 (m, 1H), 4.87-4.80 (m, 1H), 4.25 (m, 1H), 3.84-3.79 (m, 1H), 3.59 (s, 1H), 3.41-3.37 (m, 1H), 3.29-3.25 (m, 1H), 3.07 (s, 3H), 2.97-2.89 (m, 2H), 2.74-2.56 (m, 3H), 2.34 (s, 3H), 2.28 (d, 2H), 2.07-1.72 (m, 13H), 1.47-1.36 (m, 3H), 1.31-1.16 (m, 6H), 1.02-0.92 (m, 10H), 0.77 (d, 3H), 0.60-0.55 (m, 3H), 0.13 (d, 3H).

[0472] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 045, by selection of reagents, solvents and purification methods known by the skilled in the art.Amine reagent Starting intermediate Final cpd Methyl 4-aminobenzoate (CAS# 619-45-4) Int 13 Cpd 046 Methyl 4-aminobenzoate (CAS# 619-45-4) Int 22 Cpd 047 Methyl 5 -aminopicolinate (CAS# 67515-76-8) Int 13 Cpd 088Methyl 2-Aminobenzoate (CAS# 134-20-3) Int 13 Cpd 089

[0473] The following carbamate was synthesized using a similar procedure to that of Cpd 045 for steps i, ii and v, by selection of reagents, solvents and purification methods known by the skilled in the art.Amine reagent Starting intermediate Final cpd A °H L J.^^NH2Int 13 Cpd 090Int 401.6.8. Cpd 048

[0474] To a stirred solution of Int C-Cpd 045 (300 mg, 0.296 mmol, 1.0 eq.) in MeOH (20 mL) was added CSA (275 mg, 1.19 mmol, 4.0 eq.) at 0 °C and the reaction mixture was allowed to room temperature and stirred for 1 h. After reaction completion, reaction mixture was quenched with water (50 mL) and extracted with DCM (2x50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SC>4 and concentrated. The crude was purified by Prep HPLC (Column: YMC TRIART ACTUS C18 (20x100mm, 3pm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 45, 2 / 45, 10 / 80, 12 / 80, 12.1 / 98,15 / 98,15.1 / 45,20 / 45; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 18 mg of Cpd 048.

[0475] LC-MS: m / z (calcd): 971.5; m / z (obsd): 972.7 (M+H)+

[0476] ’H NMR (CDC13, 400 MHz) 5 = 15.07 (br s, 1H), 9.08 (br s, 1H), 8.47 (br s, 1H), 7.96-7.80 (m, 3H), 7.42-7.37 (m, 1H), 6.29-6.23 (m, 1H), 4.95-4.90 (m, 1H), 4.35-4.30 (m, 1H), 3.93 (m, 1H), 3.64 (m, 1H), 3.44 (m, 1H), 3.33 (m, 2H), 3.16-3.08 (m, 8H), 2.63 (m, 3H), 2.36 (s, 3H), 2.03-2.02 (m, 1H), 1.76-1.73 (m, 8H), 1.68 (m, 2H), 1.43-1.36 (m, 5H), 1.26 (m, 3H), 1.19 (m, 6H), 1.03 (br s, 9H), 0.78 (m, 3H), 0.53 (m, 3H).

[0477] To a stirred solution of Int 9 (1.0 g, 1.06 mmol, 1.0 eq.) in DCM (5 mL) was added methyl trifluoromethanesulfonate CAS# 333-27-7 (0.144 mL, 1.272 mmol, 1.2 eq.) at 0 °C and the reaction mixture was stirred at same temperature for 30 min. The reaction mixture was then treated with a solution of (R)-morpholine-2-carboxylate hydrochloride CAS# 1273577-14-2 (963 mg, 5.30 mmol, 5.0 eq.) and DIPEA (0.977 mL, 5.30 mmol, 5.0 eq.) in DCM (5 mL) at 0 °C. The reaction mixture was then stirred for lh30 at RT. After reaction completion, the reaction mixture was diluted with water (500 mL) and extracted with EtOAc (2x500 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated. The crude residue was purified by column chromatography over silica gel using a gradient of EtOAc (0-80%) in hexane to yield 600 mg of Int A-Cpd 083

[0478] LC-MS: m / z (calcd): 1119.6; m / z (obsd): 1021.0 (M+H)+1.6.9.2. Step ii: Int B-Cpd 083

[0479] A stirred solution of Int A-Cpd 083 (550 mg, 0.535 mmol, 1 eq.) in MeOH (5 mL) and THF (5 mL), cooled to 0°C, was treated with a solution of NaOH (215 mg, 5.35 mmol, 10 eq.) in water (5 mL) at 0 °C. The reaction mixture was then stirred at 55 °C for 2h. After completion, the reaction mixture was diluted with water (100 mL). The aqueous layer was neutralized to pH-7 with a 10% aq. citric acid solution, then extracted with EtOAc (2x200 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated to yield 500 mg of Int B-Cpd083.

[0480] LC-MS: m / z (calcd): 1005.5; m / z (obsd): 1006.6 (M+H)+1.6.9.3. Step Hi: Int C-Cpd 083

[0481] To a stirred solution of Int B-Cpd 083 (200 mg, 0.20 mmol, 1.0 eq.) in DMF (3 mL) were added HATU (114 mg, 0.30 mmol, 1.5 eq.), NH4CI (16 mg, 0.30 mmol, 1.5 eq.) and DIPEA (0.178 mL, 0.994 mmol, 5.0 eq.) at 0 °C and the reaction mixture was then stirred at RT for 1 h. After completion of the reaction, reaction mixture was quenched with water (100 mL) and extracted with DCM (2x 100 mL). The combined organic layers were washed with water and brine solution. The organic layer was dried over Na2SC>4 and concentrated to yield 180 mg of Int C-Cpd 083, which was used as such in the next step.

[0482] LC-MS: m / z (calcd): 1004.5; m / z (obsd): 1005.4 (M+H)+1.6.9.4. Step iv: Cpd 083

[0483] To a stirred solution of Int C-Cpd 083 (180 mg, 0.179 mmol, 1.0 eq.) in MeOH (20 mL) was added CSA (166 mg, 0.72 mmol, 4 eq.) at 0 °C and the reaction mixture was then stirred at RT for 30 min. After completion of the reaction, reaction mixture was quenched with water (100 mL) and extracted with DCM (2x 100 mL). The combined organic layers were washed with water (150 mL) and brine solution (150 mL), dried over Na2SC>4 and concentrated. The crude was purified by Prep HPLC (Column: YMC Actus Triart C18 ExRS (20x150mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 65,2 / 65,10 / 85,15.58 / 85,15.70 / 98,20.90 / 98,21 / 65,24 / 65; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 45 mg of Cpd 083.

[0484] LC-MS: m / z (calcd): 964.5; m / z (obsd): 965.7 (M+H)+

[0485] ’H NMR (CDCh-d, 400 MHz) 5 = 15.20 (m, 1H) 9.11 (br s, 1H), 8.56 (m, 1H) 6.47 (m, 1H), 6.22 (m, 1H), 5.35 (m, 1H), 4.78 (m, 1H), 4.31-4.16 (m, 3H), 3.99-3.88 (m, 3H), 3.67 (m, 1H), 3.49 (s, 1 H), 3.35 (d, 1H), 3.21-3.18 (m, 1H) 3.03 (br s, 3 H), 2.95-2.90 (m, 4H), 2.74-2.61 (m, 4H), 2.33-2.27 (m, 5H), 2.02-1.75 (m, 13H), 1.43-1.35 (m, 4 H), 1.26 (br s, 1H), 1.28-1.25 (m, 1H), 1.19 (d, 4H), 1.00 (d, 3H), 0.94 (d, 6H), 0.75 (d, 3H), 0.57 (br s, 3H), 0.09-0.06 (m, 1H).

[0486] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 083, by selection of reagents, solvents and purification methods known by the skilled in the art. When the starting amine reagent was prepared as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,... ) was used to ensure neutralization of the TFA or hydrochloride salt.Starting intermediate inAmine reagent in Step i Final cpd Step i(S)-morpholine-2 -carboxylate hydrochlorideInt 9 Cpd 084 CAS# 1439373-55-3oInt 9 Cpd 085HHCIInt 39methyl 4-aminobicyclo [2.2,2]octane- 1 -carboxylateInt 9 Cpd 104(CAS# 135908-33-7)methyl (. S')-pyrrolidinc-3 -carboxylate hydrochlorideInt 9 Cpd 112 (CAS# 1099646-61-3)methyl 4-aminobicyclo[2.1. l]hexane-l -carboxylateInt 9 Cpd 116 hydrochloride (CAS# 1638772-04-9)methyl 2-(4-amino-lH-pyrazol-l-yl) acetateInt 9 Cpd 122 hydrochloride (CAS# 6647-89-8)methyl ( / ?)-pyrrolidinc-3 -carboxylate hydrochlorideInt 9 Cpd 124 (CAS# 874964-22-4)methyl 3 -aminobicyclo [1.1.1] pentane- 1 -carboxylateInt 9 Cpd 135 hydrochloride (CAS# 676371-65-6)NH2TFAInt 9 Cpd 140 oInt 69methyl (R)-pyrrolidine-3 -carboxylate hydrochlorideInt 10 Cpd 204 (CAS# 874964-22-4)methyl 2-(4-amino-3,5-dimethyl-lH-pyrazol-l-yl)acetateInt 9 Cpd 216(CAS# 1152950-66-7)

[0487] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 083, by selection of reagents, solvents and purification methods known by the skilled in the art. When the starting amine reagent was prepared as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,... ) was used to ensure neutralization of the TFA or hydrochloride salt.StartingAmine reagent in Step i Amine reagent in Step iii intermediate Final cpd in Step iMethyl trans-4- 2-oxa-6-azaspiro[3,3]heptane aminocyclohexanecarboxylate Int 9 Cpd 129(CAS# 174-78-7)hydrochloride (CAS# 61367-07-5)methyl ( 1 s,3 s)-3 -aminocyclobutane- 1 - carboxylate hydrochloride morpholine (CAS# 110-91-8) Int 9 Cpd 172 (CAS# 1212304-86-3)methyl ( 1 r, 3 r)-3 -aminocyclobutane- 1 - Dimethylammonium chloridecarboxylate hydrochloride Int 9 Cpd 177(CAS# 506-59-2)(CAS# 74316-29-3)(R)-Methy 1 pyrrolidine-3 -carboxylatemorpholine (CAS# 110-91-8) Int 9 Cpd 178 hydrochloride (CAS# 874964-22-4)(. S)-Mcthy 1 pyrrolidine-3 -carboxylate Dimethylammonium chlorideInt 9 Cpd 179 hydrochloride (CAS# 1099646-61-3) (CAS# 506-59-2)(. S)-Mcthy 1 pyrrolidine-3 -carboxylatemorpholine (CAS# 110-91-8) Int 9 Cpd 180 hydrochloride (CAS# 1099646-61-3)(. S)-morpholinc-2 -carboxylate Dimethylammonium chlorideInt 9 Cpd 189hydrochloride (CAS# 1439373-55-3) (CAS# 506-59-2)(R) morpholine-2 -carboxylate Dimethylammonium chlorideInt 9 Cpd 190 hydrochloride (CAS# 1273577-14-2) (CAS# 506-59-2)methyl glycinate hydrochloride Dimethylammonium chlorideInt 9 Cpd 193 (CAS# 5680-79-5) (CAS# 506-59-2)methyl ( 1 r,4r)-4-aminocyclohexane- 1 - Dimethylammonium chloridecarboxylate hydrochloride Int 10 Cpd 205(CAS# 506-59-2)(CAS# 61367-07-5)1.6.10. Cpd 002 - alternative synthesis

[0488] To a stirred solution of Rifabutin (20 g, 23.612 mmol, 1.0 eq.) in DMF (200 mL) was added 2,2-dimethoxypropane (60.7 mL, 495.8 mmol, 21 eq.) and CSA (6.57 g, 28.3 mmol, 1.2 eq.) and the reaction mixture was stirred for 16 h at RT. After reaction completion, the reaction mixture was diluted with water (1000 mL), treated with NaHCO₃ (6.94 g, 82.6 mmol, 3.5 equiv.) and stirred for 30 min. The obtained solid was filtered and thoroughly dried to yield 20 g of Int A*-Cpd002

[0489] LC-MS: m / z (calcd): 886.5; m / z (obsd): 887.7 (M+H)+1.6.10.2. Step ii: Int B *-( 'pd002

[0490] To a stirred solution of Int A*-Cpd002 (20 g, 22.54 mmol, 1 eq.) in MeOH (1400 mL) was added NaOH (18.04 g, 450.9 mmol, 20 eq.) and ZnCl₂ (7.67 g, 56.3 mmol, 2.5 eq.) in water (600 mL) and the reaction mixture was stirred for 3 days at 50 °C. After reaction completion, the reaction mixture was quenched with water (500 mL) and extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with water (100 mL) and brine solution (100 mL). The organic layer dried over Na2SO4 and concentrated to yield 11.5 g of Int B*-Cpd002

[0491] LC-MS: m / z (calcd): 844.5; m / z (obsd): 845.5 (M+H)+1.6.10.3. Step iii: Int C*-Cpd002

[0492] To a stirred solution of Int B*-Cpd002 (12 g, 14.20 mmol, 1 eq.) in DCM (120 mL) was added portionwise CDT (23.29 g, 142.0 mmol, 10 eq.) at 0 °C and the resulting reaction mixture was then stirred for 16 h at 40 °C. After completion of the reaction, the mixture was quenched with water (125 mL) and extracted with EtOAc (3 x 250 mL). The combined organic layers were washed with brine solution (50 mL), dried over Na2SC>4 and concentrated to yield 10 g of Int C*-Cpd002

[0493] LC-MS: m / z (calcd): 939.5; m / z (obsd): 940.8 (M+H)+1.6.10.4. Step iv: Int D*-Cpd002

[0494] A stirred solution of Int C*-Cpd002 (12.0 g, 12.8 mmol, 1 eq.) in DCE (120 mL) was treated with triethylamine (7.18 mL, 51.12 mmol, 4 eq.) and then morpholine (4.41 mL, 51.12 mmol, 4 eq.) and the reaction mixture was stirred for 16 h at RT. After reaction completion, the reaction mixture was diluted with water (125 mL) and extracted with DCM (2 x 150 mL). The combined organic layers were washed with brine solution (100 mL), dried over Na2SC>4 and concentrated under reduced pressure. The crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-5%) in DCM to yield 4.5 g of Int D*-Cpd002

[0495] LC-MS: m / z (calcd): 957.5; m / z (obsd): 958.8 (M+H)+1.6.10.5. Step v: Int E*-Cpd002

[0496] A solution of Int D*-Cpd002 (500 mg, 0.52 mmol, 1 eq.) in MeOH (10 mL) was treated added CSA (242 mg, 1.04 mmol, 2.0 eq.) and the resulting reaction mixture was stirred at RT for 2 h. After reaction completion, the reaction mixture was quenched with ice cold water (25 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine solution, dried over Na2SO4 and concentrated to yield 450 mg of Int E*-Cpd002

[0497] LC-MS: m / z (calcd): 917.5; m / z (obsd): 918.5 (M+H)+1.6.10.6. Step vi: Cpd 002

[0498] To a stirred solution of compound Int E*-Cpd002 (180 mg, 0.23 mmol, 1.0 eq.) in MeOH (4 mL) and AcOH (0.04 mL) at RT were added 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (180 mg) and the reaction mixture was then stirred at RT under hydrogen (20 psi) in a Parr shaker for 1 hour. After completion of the reaction, the reaction mixture was filtered through a celite bed, which was washed with MeOH (30 mL). The filtrate was concentrated under reduced pressure. The crude was purified by Prep HPLC (Column: X-Select CSH phenyl hexyl (19x250mm, 5.0μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 50, 2 / 50, 8 / 80, 13 / 80, 13.1 / 98, 16 / 98, 16.1 / 50, 20 / 50; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 15 mg of Cpd 002

[0499] LC-MS: m / z (calcd): 921.5; m / z (obsd): 922.6 (M+H)+

[0500] 1H NMR (CDCl3, 400 MHz) 5 = 14.89 (m, 1 H), 9.45 (br s, 1 H), 7.98 (d, 1 H), 6.12 (d, 1 H), 5.05 (m, 1 H), 4.75 (m, 1 H), 4.67 (d, 1 H), 3.79 (s, 1 H), 3.67-3.55 (m, 4 H), 3.46-3.23 (m, 6 H), 3.08 (s, 3 H), 3.03-2.86 (m, 3 H), 2.63-2.47 (m, 3 H), 2.31-2.25 (m, 5 H), 2.15-1.98 (m, 2 H), 1.90-1.63 (m, 10 H), 1.48-1.42 (m, 1 H), 1.36-1.21 (m, 7 H), 1.01 (d, 3 H), 0.93 (d, 6 H), 0.73 (d, 3 H), 0.49 (d, 3 H), -0.07 (d, 3 H).1.6.11. Cpd 1171.6.11.1. Step i: Int A-Cpd 117

[0501] To a stirred solution of Int 9 (0.60 g, 0.636 mmol, 1.0 eq.) in DCM (10 mL) was added methyl trifluoromethanesulfonate CAS# 333-27-7 (0.086 mL, 0.763 mmol, 1.2 eq.) at 0 °C and the reaction mixture was stirred at same temperature for 30 min. The reaction mixture was then treated with a solution of Int 58 (375 mg, 1.908 mmol, 3.0 eq.) and DIPEA (0.586 mL, 3.18 mmol, 5.0 eq.) in DCM (2 mL). The reaction mixture was then stirred for Ih at RT. After reaction completion, the reaction mixture was diluted with water (150 mL) and extracted with DCM (2x150 mL). The combined organic layers were washed with brine, dried over Na2SC>4 and concentrated. The crude residue was purified by column chromatography over silica gel using a gradient of EtOAc (0-100%) in hexane to yield 400 mg of Int A-Cpd 117

[0502] LC-MS: m / z (calcd): 1070.6; m / z (obsd): 1071.5 (M+H)+1.6.11.2. Step ii: Int B-Cpd 117

[0503] To a stirred solution of Int A-Cpd 117 (400 mg, 0.373 mmol, 1 eq.) in DCM (15 mL) were added tetrakis(triphenylphosphine)palladium CAS# 14221-01-3 (86 mg, 0.075 mmol, 0.2 eq.) and 1,3-dimethylbarbituric acid CAS# 769-42-6 (87 mg, 0.056 mmol, 1.5 eq.) at 0 °C and the reaction mixture was stirred for 30 min. After completion of the reaction, reaction mixture was diluted with water (250 mL) and extracted with DCM (2 x 250 mL). The combined organic layers were washed with brine (400 mL). The organic layer was dried over Na2SC>4 and concentrated under reduced pressure. The crude residue was triturated in diethyl ether and the obtained solid was filtered and thoroughly dried to yield 450 mg of Int B-Cpd 117.

[0504] LC-MS: m / z (calcd): 986.6; m / z MW (obsd): 987.6 (M+H)+1.6.11.3. Step iii: Cpd 117

[0505] To a stirred solution of Int B-Cpd 117 (450 mg, 0.456 mmol, 1.0 eq.) in MeOH (3 mL) was added CSA (423 mg, 1.83 mmol, 4 eq.) at 0 °C and the reaction mixture was then stirred at RT for 30 min. After completion of the reaction, reaction mixture was quenched with water (100 mL) and extracted with DCM (2x 100 mL). The combined organic layers were washed with water (150 mL) and brine solution (150 mL), dried over Na2SO4 and concentrated. The crude was purified by Prep HPLC (Column: XTERRA Prep MSC18 (19x50mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 30, 2 / 30, 10 / 60, 13 / 60, 13.1 / 98, 16 / 98, 16.1 / 30, 20 / 30; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 65 mg of Cpd 117.

[0506] LC-MS: m / z (calcd): 946.5; m / z (obsd): 947.6 (M+H)+

[0507] ’H NMR (CDCh-d, 400 MHz) 5 = 15.12 (m, 1H), 9.15-9.09 (m, 1H), 8.54 (s, 1H), 8.45 (s, 1H), 6.20 (d, 1H), 4.88-4.79 (m, 2H), 4.16-3.84 (m, 8H), 3.36 (m, 1H), 3.25 (m, 1H), 3.06 (s, 6H), 2.67 (m, 5H), 2.34 (m, 5H), 2.05 (m, 4H), 1.84 (m, 4H), 1.75 (s, 7H), 1.42-1.33 (m, 4H), 1.26 (br s, 2H), 1.19 (d, 4H), 1.00-0.95 (m, 9H), 0.76 (m, 3H), 0.49 (m, 3H), 0.04 (m, 1H)

[0508] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 117, by selection of reagents, solvents and purification methods known by the skilled in the art. When the starting amine reagent was prepared as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,... ) was used to ensure neutralization of the TFA or hydrochloride salt.Starting intermediate inAmine reagent in Step i Final cpd Step iAllocxTFAJ0^NH2Int 9 Cpd 118 Int 59oAlloc-N'VS^TFA\s4 k^NH Int 9 Cpd 119 Int 57oAlloc— N / | 1TFA'N=J <, NH Int 9 Cpd 120Int 56AllocN-N'Int 9 Cpd 125 Int 60° OTFAN _ A.. A^NHAlloc— N' ~T [] Int 9 Cpd 146 Int 74° OTFAAIIOC-N Int 9 Cpd 147Int 751.6.12. Cpd 1371.6.12.1. Step i: Int A-Cpd 137

[0509] To a solution of Rifamycin S CAS# 13553-79-2 (50 g, 71.9 mmol, 1 eq.) in DMF (100 mL) was added CSA (20.0 g, 86.2 mmol, 1.2 eq.) and 2,2-dimethoxypropane (184 mL, 1.51 mol, 21 eq.) at 0°C. The reaction mixture was warmed to RT and then stirred for 3 h at RT. The reaction mixture was then quenched with ice cold water (800 mL). Obtained solids were collected by filtration and dried. This crude compound was purified by column chromatography over silica gel using a gradient of EtOAc (0-30%) in PE to yield 45 g of Int A-Cpd 137.

[0510] LC-MS: m / z (calcd): 735.3; m / z (obsd): 736.3 (M+H)+1.6.12.2. Step ii: Int B-Cpd 137

[0511] To a solution of KOH (76.25 g, 1.36 mol, 50 eq.) in ethanol (300 mL), cooled to -10°C, was added portionwise Int A-Cpd 137 (20.0 g, 27.18 mmol, 1 eq.). The reaction mixture was then stirred at -10°C for 64 h. After reaction completion, the reaction was quenched with a 10% Citric acid aqueous solution to adjust the pH to 6 and stirred for 1 h. The obtained solid was collected by filtration and dried. This crude compound was purified by column chromatography over silica gel using a gradient of EtOAc (0-50%) in hexane to yield 5.3 g of Int B-Cpd 137.

[0512] LC-MS: m / z (calcd): 693.3; m / z (obsd): 692.4 (M-H)’1.6.12.3. Step Hi: Int C-Cpd 137

[0513] To a stirred solution of Int B-Cpd 137 (2.0 g, 2.89 mmol, 1.0 eq.) in DCM (20 mL) was added CDT (0.95 g, 5.78 mmol, 2.0 eq.) at RT. The reaction mixture was then heated at 40 °C and stirred for 24 h. Another portion of CDT (0.95 g, 5.78 mmol, 2.0 eq.) was then added at RT and the reaction mixture was stirred at 40 °C for another 24 h. After reaction completion, the reaction was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over Na2SC>4 and concentrated to yield 1.9 g of Int C-Cpd 137, which was used as such.

[0514] LC-MS: m / z (calcd): 788.3; m / z (obsd): 789.4 (M+H)+1.6.12.4. Step iv: Int D-Cpd 137

[0515] To a solution of Int C-Cpd 137 (1.9 g, 2.41 mmol, 1 equiv.) in DCM (30 mL) was added morpholine (0.315 g, 3.61 mmol, 1.5 eq.) at RT and the reaction mixture was stirred for 16 h at RT. After reaction completion, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 x50 mL). The combined organic layers were dried over Na2SC>4 and concentrated. The obtained crude was purified by column chromatography over silica gel using a gradient of EtOAc (0-50%) in PE to yield 1.4 g oflnt D-Cpd 137.

[0516] LC-MS: m / z (calcd): 806.4; m / z (obsd): 805.1 (M-H)

[0517] ’HNMR (DMSO-de, 400 MHz) 5 = 12.85 (s, 1H), 10.07 (s, 1H), 7.65 (s, 1H), 6.07-5.87 (m, 4H), 5.12-5.07 (m, 1H), 4.74-4.72 (m, 1H), 3.58-3.48 (m, 5H), 3.36-3.33 (m, 5H), 3.04-3.00 (m, 1H), 2.82 (s, 1H), 2.22-1.92 (m, 10H), 1.70-1.45 (m, 2H), 1.08 (m, 3H), 0.81-0.43 (m, 17H)1.6.12.5. Step v: Int E-Cpd 137

[0518] To a stirred solution oflnt D-Cpd 137 (16.0 g, 19.83 mmol, 1 eq.) in methanol (200 mL) at RT was added 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (16 g) and cinchonidine CAS# 485-71-2 (3.50 g, 11.90 mmol, 0.6 eq.) and the reaction mixture was then stirred at RT under hydrogen (30 psi) in a Parr shaker for 3h. After completion of the reaction, the reaction mixture was filtered through a celite bed, which was washed with THF (2 x 100 mL). The filtrate was concentrated under reduced pressure. The crude residue which was purified by column chromatography over silica gel using a gradient of MeOH (0-10%) in DCMto yield 7.0 g oflnt E-Cpd 137-peak 1 (first eluting) and 5.0 g oflnt E-Cpd 137-peak 2 (second eluting).

[0519] LC-MS Int E-Cpd 137-peak 1 (first eluting): m / z (calcd): 812.4; m / z (obsd): 811.6 (M-H)’1.6.12.6. Step vi: Int F-Cpd 137

[0520] To a stirred solution of Int E-Cpd 137-peak 1 (5.0 g, 6.15 mmol, 1 eq.) in DCM (50 mL) was added MnO2(5.34 g, 61.50 mmol, 10 eq.) at RT and the reaction mixture was stirred at RT for 4 h. After reaction completion, the reaction mixture was filtered through a celite bed and washed with methanol (2x100 mL). The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-10%) in DCM to yield 3.0 g oflnt F-Cpd 137.

[0521] LC-MS: m / z (calcd): 810.4; m / z (obsd): 809.6 (M-H)’1.6.12.7. Step vii: Int G-Cpd 137

[0522] To a stirred solution of Int F-Cpd 137 (5.0 g, 6.17 mmol, 1 eq.) in DMF (50 mL) were added sodium azide (1.60 g, 24.66 mmol, 2 eq.) at RT and the reaction mixture was further stirred at 35 °C for 16 h. After completion of the reaction, the reaction mixture was quenched with ice cold water (50 mL), extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over Na2SC>4 and concentrated. The obtained crude was purified by column chromatography over silica gel using a gradient of MeOH (0-10%) in DCMto yield 1.0 g of Int G-Cpd 137.

[0523] LC-MS: m / z (calcd): 825.4; m / z (obsd): 824.6 (M-H)1.6.12.8. Step viii: Int H-Cpd 137

[0524] A stirred solution of Int G-Cpd 137 (1.0 g, 1.21 mmol, 1 eq.) in methanol (15 mL) was treated with a 7N ammonia solution in MeOH (3 mL) at 0 °C. The resulting reaction mixture was then stirred at RT for 3 days. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield 1.0 g of Int H-Cpd 137, which was used as such.

[0525] LC-MS: m / z (calcd): 824.4; m / z (obsd): 823.0 (M-H)1.6.12.9. Step ix: Int I-Cpd 137

[0526] To a stirred solution of Int H-Cpd 137 (1.0 g, 1.21 mmol, 1 eq.) in THF (10 mL) were added Int 70 (284 mg, 1.82 mmol, 1.5 eq.), NH4OAc (234 mg, 3.03 mmol, 2.5 eq.) and zinc powder (198 mg, 3.03 mmol, 2.5 eq.) at RT and the resulting reaction mixture was stirred at RT for 6 h. After completion of the reaction,the reaction mixture was quenched with a sat. aq. NH4CI solution (15 mL) and extracted with DCM (2 x 25 mL). The combined organic layers were dried overNa2SO4 and concentrated. The obtained crude was purified by column chromatography over silica gel using a gradient of MeOH (0-10%) in DCM to yield 110 mg oflnt I-Cpd 137.

[0527] LC-MS: m / z (calcd): 977.5; m / z (obsd): 978.3 (M+H)+1.6.12.10. Step x: Cpd 137

[0528] To a stirred solution of Int I-Cpd 137 (110 mg, 0.112 mmol, 1 eq.) in MeOH (5 mL) was added CSA (104 mg, 0.45 mmol, 4 eq.) at 0 °C. The reaction mixture was then stirred at RT for 1 h. After reaction completion, the reaction mixture was quenched with ice cold water (25 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude was purified by Prep HPLC (Column: X-BRIDGE C18 PREP SHIELD OBD (19x250mm, 5μm); Mobile phase A: 0.1% FA in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 25, 2 / 25, 10 / 55, 11.22 / 55, 11.28 / 98, 27.80 / 98, 18 / 25, 21 / 25; Temperature: Ambient). Pure fractions were concentrated and lyophilized to yield 23 mg of Cpd 137.

[0529] LC-MS: m / z (calcd): 937.5; m / z (obsd): 938.7 (M+H)+

[0530] ’H NMR (CDCh-d, 400 MHz) 5 = 14.77 (br s, 1H), 9.28 (br s, 1H), 8.04 (s, 1H), 6.11 (d, 1H), 5.02 (m, 1H), 4.74 (m, 1H), 4.67 (m, 1H), 3.80 (s, 1H) 3.72 (m, 1H), 3.66-3.56 (m, 2H), 3.42 (m, 6H), 3.20 (br s, 1H), 3.08 (s, 3H), 3.05-2.98 (m, 2H), 2.78 (m, 2H), 2.59-2.49 (m, 2H), 2.31 (s, 5H), 2.01 (m, 2H), 1.76 (s, 3H), 1.73-1.53 (m, 12H), 1.37-1.26 (m, 10 H), 1.01 (d, 3H), 0.81 (m, 2H), 0.72 (m, 3H), 0.49 (d, 3H), 0.08 (d, 1H)

[0531] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 137, by selection of reagents, solvents and purification methods known by the skilled in the art.Ketone reagent in Step ix Final cpd OHCpd 138 Int 710 / — \ y— NH20=^ N — 'Cpd 139Int 721.6.13. Cpd 1481.6.13.1. Step i: Int A-Cpd 148

[0532] Int A-Cpd 148 was synthesized according to the procedure described in step i of Cpd 022 (i.e. General procedure B - MeOTf mediated carbamate formation) starting from imidazole Int 9 and using methyl (lr,4r)-4-aminocyclohexane-l -carboxylate hydrochloride CAS# 61367-07-5 as amine reagent in the presence of DIPEA.

[0533] LC-MS: m / z (calcd): 1031.6; m / z (obsd): 1032.3 (M+H)+1.6.13.2. Step ii: Int B-Cpd 148

[0534] To a stirred solution of Int A-Cpd 148 (800 mg, 0.775 mmol, 1.0 eq.) in THF (10 m ), water (5 m ) and MeOH (5 mb) was added lithium hydroxide monohydrate (98 mg, 2.32 mmol, 3 eq.) at RT and the resulting reaction mixture was then stirred for 4 h at RT. After reaction completion, the volatiles were evaporated and the crude was diluted with water (10 mb) and pH was brought to 4 by addition of a 10% aq. citric acid solution. The obtained solids were filtered off and thoroughly dried to yield 550 mg of Int B-Cpd 148 which was used as such in the next step.

[0535] LC-MS: m / z (calcd): 1017.6; m / z (obsd): 1018.5 (M+H)+1.6.13.3. Step Hi: Int C-Cpd 148

[0536] To a stirred solution of Int B-Cpd 148 (250 mg, 0.246 mmol, 1.0 eq.) in DMF (5 mL) were added DIPEA (0.220 mL, 1.23 mmol, 5.0 eq.) and HATU (140 mg, 0.37 mmol, 1.5 eq.) at 0°C and the reaction mixture was then stirred for 10 minutes at RT. Mixture was cooled to 0°C, then treated with 2-Oxa-7-azaspiro [3.5] nonane (CAS# 241820-91-7) (47 mg, 0.368 mmol, 1.5 eq.) and the resulting solution was then stirred 2h at RT. After completion of the reaction, the reaction mixture was quenched with ice-cold water (10 mL) under vigorous stirring. The obtained solids were filtered off and thoroughly dried to yield 210 mg of Int C-Cpd 148 which was used as such in the next step.

[0537] LC-MS: m / z (calcd): 1126.7; m / z (obsd): 1127.4 (M+H)+1.6.13.4. Step iv: Cpd 148

[0538] To a stirred solution of Int C-Cpd 148 (180 mg, 0.16 mmol, 1 eq.) in MeOH (10 mL) was added CSA (232 mg, 1.00 mmol, 4 eq.) at 0 °C. The reaction mixture was then stirred at RT for 30 minutes. After reaction completion, the reaction mixture was quenched with ice cold water (10 mL) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with water, then brine, dried over Na2SO4 and concentrated. The crude was purified by Prep HPLC (Column: X-BRIDGE C18 (19x250mm, 5μm); Mobile phase A: 0.1% FA in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 60, 2 / 60, 10 / 80, 13.4 / 80, 13.5 / 98, 18 / 98, 18.1 / 60, 21 / 60; Temperature: Ambient). Pure fractions were concentrated and lyophilized to yield 50 mg of Cpd 148.

[0539] LC-MS: m / z (calcd): 1086.6; m / z (obsd): 1087.7 (M+H)+

[0540] ’HNMR (CDCh-d, 400 MHz) 5 = 15.15 (s, 1H), 9.09 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 6.22 (d, 1H), 4.85-4.75 (m, 1H), 4.59 (d, 1H), 4.47 (d, 4H), 4.35 (d, 1H), 4.22-4.05 (m, 1H), 3.70 (s, 1H), 3.50-3.34 (m, 6H), 3.28-3.22 (m, 1H), 3.08 (s, 2H), 3.05-2.85 (m, 4H), 2.75-2.55 (m, 3H), 2.48-2.38 (m, 1H), 2.31 (s,3H), 2.28 (d, 2H), 2.12-1.95 (m, 5H), 1.87-1.74 (m, 15H), 1.69 (d, 3H), 1.45-1.21 (m, 5H), 1.19-1.10 (m, 6H), 1.01 (d, 3H), 0.93 (d, 6H), 0.75 (d, 3H), 0.50 (d, 3H), 0.07 (d, 3H)

[0541] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 148, by selection of reagents, solvents and purification methods known by the skilled in the art. When the starting amine reagent was prepared as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,... ) was used to ensure neutralization of the TFA or hydrochloride salt.Amine reagent in Step iii Final cpd A-Methyltetrahydro-2H-pyran-4-amine (CAS# 220641-87-2) Cpd 1491 -methylpiperazine (CAS# 109-01-3) Cpd 150 2,2-Dimethylmorpholine hydrochloride (CAS# 167946-94-3) Cpd 151(S)-Pyrrolidin-3-ol (CAS# 100243-39-8) Cpd 152 3, 3 -dimethylazetidine hydrochloride (CAS# 89381-03-3) Cpd 153 cyclopropyl(piperazin-l-yl)methanone (CAS# 59878-57-8) Cpd 164 3, 3 -difluoroazetidine hydrochloride (CAS# 288315-03-7) Cpd 165 3, 3 -difluoropyrrolidine hydrochloride (CAS# 163457-23-6) Cpd 166 (S)-N-methyltetrahydrofuran-3-amine hydrochloride (CAS# 1292324-44-7) Cpd 167(2. S'.6 / ?)-2.6-dimcthvlmorpholinc (CAS# 6485-55-8) Cpd 168 N-methylethanamine hydrochloride (CAS# 624-60-2) Cpd 185 3-Methylazetidin-3-ol hydrochloride (CAS# 124668-46-8) Cpd 194 1 -Ethyl- lH-pyrazol-4-amine (CAS# 876343-24-7) Cpd 195 (7?)-Pyrrolidin-3-ol (CAS# 2799-21-5) Cpd 196( / ?)-N-mcthvltctrahvdrofiiran-3-aminc hydrochloride (CAS# 1292324-63-0) Cpd 197

[0542] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 148, by selection of reagents, solvents and purification methods known by the skilled in the art. When the starting amine reagent was prepared as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,... ) was used to ensure neutralization of the TFA or hydrochloride salt.Final Amine reagent in Step i Amine reagent in Step iiicpd Methyl cis-4-Aminocyclohexanecarboxylate Dimethylammonium chlorideCpd 173 Hydrochloride (CAS# 61367-16-6) (CAS# 506-59-2)Methyl cis-4-Aminocyclohexanecarboxylate (R)-tetrahydrofuran-3-amineCpd 174 Hydrochloride (CAS# 61367-16-6) (CAS# 111769-26-7)Methyl cis-4-Aminocyclohexanecarboxylate (S)-tetrahydrofuran-3-amineCpd 175 Hydrochloride (CAS# 61367-16-6) (CAS# 104530-79-2)Methyl cis-4-Aminocyclohexanecarboxylate (. S)-A-Mcthyltctrahydrofuran-3-amincCpd 186 Hydrochloride (CAS# 61367-16-6) hydrochloride (CAS# 1292324-44-7) Methyl cis-4-Aminocyclohexanecarboxylate 2-oxa-6-azaspiro [3.4] octaneCpd 187 Hydrochloride (CAS# 61367-16-6) (CAS# 220290-68-6)Methyl cis-4-Aminocyclohexanecarboxylate N-methylethanamine hydrochlorideCpd 191Hydrochloride (CAS# 61367-16-6) (CAS# 624-60-2)methyl 4-aminobicyclo [2.2.2] octane- 1- Dimethylammonium chlorideCpd 199 carboxylate (CAS# 135908-33-7) (CAS# 506-59-2)methyl 4-aminobicyclo [2.2.2] octane- 1- morpholine (CAS# 110-91-8) Cpd 200 carboxylate (CAS# 135908-33-7) / ^NH2,0^0 ™Dimethylammonium chlorideCpd 201 o (CAS# 506-59-2)Int 69 / ^NH2,0^0 ™morpholine (CAS# 110-91-8) Cpd 202 oInt 69Methyl cis-4-Aminocyclohexanecarboxylate 8-oxa-2-azaspiro [4.5] decaneCpd 214 Hydrochloride (CAS# 61367-16-6) (CAS# 310-93-0)Methyl cis-4-Aminocyclohexanecarboxylate ( / ?)-N-mcthyltctrahydrofuran-3-amincCpd 215Hydrochloride (CAS# 61367-16-6) (CAS# 1292324-63-0)

[0543] To a stirred solution of Int 5 (1.0 g, 1.178 mmol, 1 eq.) in DCE (15 mL) were added methyl 5-aminonicotinate CAS# 36052-25-2 (538 mg, 3.533 mmol, 3.0 eq.) and CDI (573 mg, 3.533 mmol, 3.0 eq.) at RT and the reaction mixture was then stirred at 50° C for 72 h. After completion, the reaction mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layer was washed with brine (200 mL), dried over Na2SC>4 and concentrated. The obtained crude was purified by column chromatography over silica gel using a gradient of EtOAc (20-70%) in hexane to yield 1.0 g of Int A-Cpd 160

[0544] LC-MS: m / z (calcd): 1026.5; m / z (obsd): 1027.5 (M+H)+1.6.14.2. Step ii: Int B-Cpd 160

[0545] To a stirred solution of Int A-Cpd 160 (950 mg, 0.925 mmol, 1.0 eq.) in THF (10 mL) and water (3 mL) was added lithium hydroxide monohydrate (194 mg, 4.62 mmol, 5 eq.) at 0°C and the resulting reaction mixture was then stirred for 1 h at RT. After reaction completion, the reaction mixture was diluted with water (100 mL) and washed with DCM (50 mL). The pH of the aqueous layer was brought to 4 by addition of a 10% aq. citric acid solution and the aqueous layer was extracted with DCM (2 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over Na2SC>4 and concentrated to yield 650 mg of Int B-Cpd 160 which was used as such in the next step.

[0546] LC-MS: m / z (calcd): 1012.5; m / z (obsd): 1013.4 (M+H)+1.6.14.3. Step Hi: Int C-Cpd 160

[0547] To a stirred solution of Int B-Cpd 160 (650 mg, 0.642 mmol, 1.0 eq.) in DMF (8 mL) were added DIPEA (0.576 mL, 3.21 mmol, 5.0 eq.) and HATU (366 mg, 0.962 mmol, 1.5 eq.) at 0°C and the reaction mixture was then stirred for 30 minutes at RT. Mixture was cooled to 0°C, then treated with ammonium chloride (52 mg, 0.962 mmol, 1.5 eq.) and the resulting solution was stirred Ih at RT. After completion of the reaction, the reaction mixture was quenched with ice-cold water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was washed with water, then brine, dried over Na2SC>4 and concentrated to yield 500 mg of Int C-Cpd 160 which was used as such in the next step.

[0548] LC-MS: m / z (calcd): 1011.5; m / z (obsd): 1012.4 (M+H)+1.6.14.4. Step iv: Cpd 160

[0549] To a stirred solution of Int C-Cpd 160 (450 mg, 0.445 mmol, 1 eq.) in MeOH (10 mL) was added CSA (413 mg, 1.78 mmol, 4 eq.) at 0 °C and the reaction mixture was then stirred at RT for 1 h. After reaction completion, the reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layers were washed with water, then brine, dried over Na2SC>4 and concentrated. The crude was purified by Prep HPLC (Column: X-BRIDGE C18 (19x250mm, 5μm); Mobile phase A: 10 mM ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 13 mL / min; Gradient: (Time / % OF B): 0 / 20, 2 / 50, 10 / 70, 14 / 70, 14.1 / 99, 18.90 / 99, 19 / 20, 22 / 50; Temperature: Ambient). Pure fractions were concentrated and lyophilized to yield 70 mg of Cpd 160.

[0550] LC-MS: m / z (calcd): 971.5; m / z (obsd): 972.5 (M+H)+

[0551] ’H NMR (CDCh-d, 400 MHz) 5 = 16.01 (s, 1H), 9.78 (s, 1H), 9.38 (s, 1H), 9.27 (br s, 1H) 8.67 (d, 1H), 8.63 (d, 1H), 8.28 (br s, 1H), 8.08 (br s, 1H), 7.54 (br s, 1H) 6.17 (m, 1H), 5.00 (m, 2H), 4.77 (m, 1H), 4.42 (br s, 1H) 3.48-3.44 (m, 2H), 3.24 (s, 1H), 3.21 (s, 1H), 3.03 (m, 1H), 2.84 (s, 1H), 2.74 (m, 4H), 2.26-2.20 (m, 7H), 1.81-1.85 (m, 1H), 1.69 (s, 3H), 1.60 (m, 5H), 1.42 (m, 3H), 1.29-1.22 (m, 3H), 1.10 (m, 4H), 0.99 (m, 1H), 0.92 (d, 7H), 0.86 (m, 4H), 0.78 (m, 3 H), 0.69-0.66 (m, 1H) 0.62-0.58 (m, 1H), 0.40 (m, 3H), 0.21-0.16 (m, 1H) 0.07 (d, 3H)

[0552] The following carbamates compounds were synthesized using a similar procedure to that of Cpd 160, by selection of reagents, solvents and purification methods known by the skilled in the art.Amine reagent in Step iii Final cpd Methyl 6-aminopyridine-2-carboxylate (CAS# 36052-26-3) Cpd 161 Methyl 5 -amino- 1 -methyl- lH-pyrazole-3 -carboxylateCpd 217 (CAS# 92406-53-6)Ethyl 4-aminopyrimidine-2 -carboxylate (CAS# 71470-41-2) Cpd 218

[0553] The following carbamate was synthesized using a similar procedure to that of Cpd 160 for steps i and iv, by selection of reagents, solvents and purification methods known by the skilled in the art. When the starting amine reagent was prepared as a TFA or hydrochloride salt, an excess of amine (like triethylamine, DIPEA,... ) was used to ensure neutralization of the TFA or hydrochloride salt.Amine reagent Final cpd5-Pyrimidinamine (CAS# 591-55-9) Cpd 1624-Aminopyrimidine (CAS# 591-54-8) Cpd 1633-Aminopyridazine (CAS# 5469-70-5) Cpd 181 Thiazol-4-amine hydrochloride (CAS# 59134-95-1) Cpd 183pyrazin-2-amine (CAS# 5049-61-6) Cpd 1981.6.15. Cpd 2201.6.15.1. Step i: Int A-Cpd 220

[0554] Int A-Cpd 220 was synthesized according to the procedure described in step i of Cpd 022 (i.e. General procedure B - MeOTf mediated carbamate formation) starting from imidazole Int 9 and using 6-(Benzyloxy)pyridin-3 -amine (CAS# 75926-65-7) as amine reagent in the presence of DIPEA.

[0555] LC-MS: m / z (calcd): 1074.6; m / z (obsd): 1075.4 (M+H)+1.6.15.2. Step ii: Int B-Cpd 220

[0556] To a stirred solution of Int A-Cpd 220 (350 mg, 0.325 mmol, 1.0 eq.) in MeOH (10 mL) was added 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (150 mg) at room temperature. The resulting suspension was placed under a H2 atmosphere (balloon pressure) and then stirred for 1 h. After reaction completion, the reaction mixture was filtered over a celite bed, which was then rinsed with MeOH (20 mL).The filtrate was concentrated and the obtained residue was thoroughly dried to yield 300 mg of Int B-Cpd 220 which was used as such in the next step.

[0557] LC-MS: m / z (calcd): 984.5; m / z (obsd): 985.4 (M+H)+1.6.15.3. Step iii: Cpd 220HO

[0558] To a stirred solution of Int B-Cpd 220 (250 mg, 0.25 mmol, 1 eq.) in MeOH (5 mL) was added CSA (236 mg, 1.00 mmol, 4 eq.) at 0 °C. The reaction mixture was then stirred at RT for 30 minutes. After reaction completion, the reaction mixture was quenched with ice cold water and extracted with DCM. The combined organic layers were washed with water, then brine, dried over Na2SC>4 and concentrated. The crude was purified by Prep HPLC (Column: X Bridge Prep C18 OBD (19x100mm, 5μm); Mobile phase A: 1 mM ammonium bicarbonate in water; Mobile phase B: Acetonitrile; Flow rate: 12 mL / min; Gradient: (Time / % OF B): 0 / 35, 2 / 35, 10 / 85, 15 / 85, 15.1 / 98,22 / 98, 22.1 / 35, 26 / 35; Temperature: Ambient). Pure fractions were concentrated and lyophilized to yield 60 mg of Cpd 220.

[0559] LC-MS: m / z (calcd): 944.5; m / z (obsd): 945.4 (M+H)+

[0560] ’HNMR (CDCh-d, 400 MHz) 5 = 15.17 (s, 1H), 9.19 (br s, 1H), 8.50 (br s, 1H), 7.61 (br s, 1H), 7.31 (m, 2H), 6.59 (m, 2H), 6.26 (d, 1H), 4.87-4.81 (m, 1H), 4.23 (m, 1H), 3.77 (br s, 1H), 3.56 (s, 1H), 3.37 (m, 1 H), 3.29 (m, 1H), 3.04 (br s, 4H), 2.95-2.91 (m, 2H), 2.68 (m, 3 H), 2.30 (s, 5H), 2.01 (br s, 3H), 1.89-1.83 (m, 5H), 1.80 (br s, 1H), 1.68 (br s, 1H), 1.73-1.66 (m, 3H), 1.65 (br s, 1H), 1.40 (m, 3H), 1.30-1.25 (m, 2H) 1.19 (d, 3H), 1.16 (m, 1H), 1.00 (d, 3H), 0.93 (d, 6H) 0.76 (d, 3H), 0.54 (m, 3H), 0.11 (d, 3H)1.6.16. Cpd 0491.6.16.1. Step i: Int A-Cpd 049

[0561] To a stirred solution of 6-(methoxycarbonyl)nicotinic acid CAS# 17874-76-9 (623 mg, 3.44 mmol, 5 eq.) and 2-Methyl-6-nitrobenzoic anhydride CAS# 434935-69-0 (1184 mg, 3.44 mmol, 5 eq.) in DCM (18 mL) at RT, was added triethylamine (1.45 mL, 10.32 mmol, 15 eq.) and the resulting mixture was stirred for 30 min. The reaction mixture was then treated with a solution of Int 11 (700 mg, 0.688 mmol, 1 eq.) in DCM (2 mL) and a solution of DMAP (420 mg, 3.44 mmol, 5 eq.) in DCM (2 mL) (simultaneous addition). The reaction mixture was then stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, brine, dried over Na2SC>4 and concentrated. The crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-5%) in DCM to yield 650 mg of Int A-Cpd 049.

[0562] LC-MS: m / z (calcd): 1095.5; m / z (obsd): 1096.2 (M+H)+1.6.16.2. Step ii: Int B-Cpd 049

[0563] To a stirred solution of Int A-Cpd 049 (350 mg, 0.319 mmol, 1 eq.) in DCM (30 mL) were added tetrakis(triphenylphosphine)palladium CAS# 14221-01-3 (74 mg, 0.064 mmol, 0.2 eq.) and 1,3-dimethylbarbituric acid CAS# 769-42-6 (100 mg, 0.639 mmol, 2 eq.) at 0 °C and the reaction mixture was stirred for 30 min. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-5%) in DCM to yield 320 mg of Int B-Cpd 049.

[0564] LC-MS: m / z (calcd): 1011.5; m / z (obsd): 1012.4 (M+H)+1.6.16.3. Step iii: Int C-Cpd 049

[0565] A stirred solution of Int B-Cpd 049 (320 mg, 0.316 mmol, 1 eq.) in THF (20 mL) and MeOH (5 mL) was treated with a solution of Lithium hydroxide monohydrate (26.5 mg, 0.632 mmol, 2 eq.) in water (2 mL) at 0 °C. After reaction completion, the reaction mixture was diluted with water (50 mL) and the pH of the aqueous layer was brought to pH = 7 by addition of a 10% aq. citric acid solution. The mixture was then extracted with extracted with EtOAc (2x100 mL). The combined organic layers were washed with brine solution (100 mL), dried over Na₂SO₄ and concentrated to yield 300 mg of Int C-Cpd 049.

[0566] LC-MS: m / z (calcd): 999.5; m / z (obsd): 998.4 (M-H)’1.6.16.4. Step iv: Int D-Cpd 049

[0567] To a stirred solution of Int C-Cpd 049 (280 mg, 0.281 mmol, 1 eq.) in DMF (20 mL), were added HATU (213 mg, 0.561 mmol, 2 eq.), NH4CI (75 mg, 1.40 mmol, 5 eq.) and DIPEA (217 mg, 1.68 mmol, 6 eq.) at 0 °C. The resulting reaction mixture was then allowed to RT and stirred for 4 h. After completion of the reaction, reaction mixture was quenched with water (50 mL) and extracted with DCM (2x 50 mL). The combined organic layers were washed with water and brine solution. The organic layer was dried over Na2SC>4 and concentrated to yield 280 mg of Int D-Cpd 049.

[0568] LC-MS: m / z (calcd): 996.5; m / z MW (obsd): 997.3 (M+H)+

[0569] To a stirred solution of Int D-Cpd 049 (250 mg, 0.251 mmol, 1.0 eq.) in MeOH (30 mL) was added CSA (233 mg, 1.0 mmol, 4.0 eq.) at 0 °C and the reaction mixture was allowed to RT and stirred for 30 minutes. After reaction completion, reaction mixture was quenched with water (50 mL) and extracted with DCM (2x50 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SC>4 and concentrated. The crude was purified by Prep HPLC (Column: X BRIDGE C8 (19x250mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 55, 2 / 55, 10 / 75, 14 / 75, 14.1 / 99, 18 / 99, 18.1 / 55, 22 / 55; Temperature: Ambient). Pure fractions were concentrated and lyophilized to yield 35 mg of Cpd 049.

[0570] LC-MS (method Aragen D): m / z (calcd): 956.5; m / z (obsd): 957.8 (M+H)+

[0571] 1HNMR (CDC13, 400 MHZ) 8 = 15.20 (br s, 1H), 9.21 (s, 1H), 9.11 (d, 1H), 8.59 (s, 1H), 8.41 (m, 1H), 8.26 (d, 1H), 7.85 (m, 1H), 6.24 (d, 1H), 5.61 (m, 1H), 4.80 (m, 1H), 4.54 (m, 1H), 3.54-3.50 (m, 1H), 3.38 (d, 1H), 3.33 (d, 1H), 3.21 (m, 1H), 3.01-2.91 (m, 3H), 2.88 (s, 3H), 2.75-2.58 (m, 3H), 2.41 (s, 3H), 2.30 (d, 2H), 2.17 (m, 1H), 2.09-2.00 (m, 3H), 1.94-1.74 (m, 5H), 1.73 (s, 3H), 1.68 (m, 1H), 1.51-1.38 (m, 3H), 1.31-1.11 (m, 6H), 0.99-0.91 (m, 9H), 0.77 (d, 2H), 0.66 (d, 3H), 0.16 (d, 3H).

[0572] The following esters compounds were synthesized using a similar procedure to that of Cpd 049, by selection of reagents, solvents and purification methods known by the skilled in the art.Acid reagent Starting intermediate Final cpdN^iInt 11 Cpd 050 02-(Methoxycarbonyl)isonicotinic acid (CAS# 24195-10-6)^°Y°W 0HInt 11 Cpd 0516-(methoxycarbonyl)picolinic acid (CAS# 7170-36-7)

[0573] Cpd 052 was synthesized using a similar procedure to that of Cpd 049 for steps i to iv and using General Procedure E (step ii - Cpd 022) for the final acetonide deprotection, by selection of reagents, solvents and purification methods known by the skilled in the art.Acid reagent Starting intermediate Final cpdN^A^OH Int 11 Cpd 052 05-(Methoxycarbonyl)nicotinic acid (CAS# 5027-65-6)

[0574] Cpd 053 and Cpd 054 were synthesized using a similar procedure to that of Cpd 049 for steps i, ii and v, by selection of reagents, solvents and purification methods known by the skilled in the art.Acid reagent Starting intermediate Final cpd o., A°HInt 11 Cpd 053 Nicotinic acid N-oxide (CAS# 2398-81-4)o oH2NInt 12 Cpd 054 3-(Aminocarbonyl)benzoic acid (CAS# 4481-28-1)OH— o Int 12 Cpd 0552-Methoxyisonicotinic acid (CAS# 105596-63-2)1.6.17. Cpd 0561.6.17.1. Step i: Int A-Cpd 056

[0575] A stirred solution of 3 -(methoxy carbonyl) benzoic acid CAS# 1877-71-0 (443 mg, 2.46 mmol, 5 eq.) in DCM (20 mb) was treated with 2-methyl-6-nitrobenzoic anhydride CAS# 434935-69-0 (0.881 g, 2.558 mmol, 5.2 eq.) and triethylamine (1.037 mb, 7.38 mmol, 15 eq.) and then stirred for 20 min at RT.The reaction mixture was then treated with a solution of Int 11 (500 mg, 0.492 mmol, 1 eq.) in DCM (10 mL) and a solution of DMAP (240 mg, 1.97 mmol, 4 eq.) in DCM (10 mL) (simultaneous addition). The reaction mixture was stirred at RT for 6 h. After completion of the reaction, the solvents were evaporated and the crude residue was purified by column chromatography over silica gel using a gradient of EtOAc (0-70%) in hexane to yield 400 mg Int A-Cpd 056.

[0576] LC-MS: m / z (calcd): 1256.6; m / z (obsd): 1257.6 (M+H)+1.6.17.2. Step ii: Int B-Cpd 056

[0577] To a stirred solution of Int A-Cpd 056 (400 mg, 0.318 mmol, 1 eq) in DCM (10 mL) were added 1,3 -dimethylbarbituric acid CAS# 769-42-6 (223 mg, 1.43 mmol, 4.5 eq.) and tetrakis(triphenylphosphine) palladium CAS# 14221-01-3 (37 mg, 0.032 mmol, 0.1 eq.) at 0 °C the reaction mixture was stirred for 30 min at same temperature. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with DCMc (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SC>4 and concentrated under reduced pressure to get 350 mg of crude Int B-Cpd 056 which was used as such in the next step.

[0578] LC-MS: m / z (calcd): 1172.6; m / z (obsd): 1173.0 (M+H)+1.6.17.3. Step Hi: Int C-Cpd 056

[0579] A stirred solution of Int B-Cpd 056 (330 mg, 0.281 mmol, 1 eq) in THF (6 mL) and MeOH (2 mL) was treated with a solution of lithium hydroxide monohydrate (24 mg, 0.562 mmol, 2 eq.) in water (2 mL) at 0 °C. temperature, allow the reaction mixture to stirred at room temperature for 2 h. After reaction completion, the reaction mixture was diluted with water (3 mL) and the pH of the aqueous layer was brought to pH = 7 by addition of a 10% aq. citric acid solution. The mixture was then extracted with extracted with EtOAc (2x50 mL). The combined organic layers were washed with brine solution (20 mL), dried over Na2SO4 and concentrated to yield 300 mg of crude Int C-Cpd 056 which was used as such in the next step.

[0580] LC-MS: m / z (calcd): 996.5; m / z (obsd): 997.3 (M+H)+1.6.17.4. Step iv: Int D-Cpd 056

[0581] To a stirred solution of Int C-Cpd 056 (330 mg, 0.33 mmol, 1 eq.) in DMF (8 mL) were added DIPEA (0.267 mL, 1.655 mmol, 5 eq), HATU (377.4 mg, 0.993 mmol, 3 eq) and NH₄Cl (53 mg, 0.993 mmol, 3 eq) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, reaction mixture was diluted with water (20 mL) and obtained solid was filtered and thoroughly dried to yield 200 mg of crude Int D-Cpd 056 which was used as such in the next.

[0582] LC-MS: m / z (calcd): 995.5; m / z (obsd): 996.2 (M+H)+1.6.17.5. Step v: Cpd 056

[0583] To a stirred solution of Int D-Cpd 056 (180 mg, 0.181 mmol, 1 eq) in MeOH (10 mL) was added CSA (84 mg, 0.36 mmol, 2.0 eq.) at 0 °C and the reaction mixture was allowed to room temperature and stirred for 2 h. After reaction completion, reaction mixture was quenched with a sat. NaHCO3 aq. solution (15 mL) and extracted with DCM (3x30 mL). The combined organic layers were washed with water (50 mL), dried over Na2SC>4 and concentrated. The crude was purified by Prep HPLC (Column: XTERRA Prep MSC18 (19x50mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 30,2 / 30,10 / 70,12.20 / 70,12.30 / 98,14.90 / 98,14.10 / 30,16 / 30; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 40 mg of Cpd 056.

[0584] LC-MS: m / z (calcd): 955.5; m / z (obsd): 956.8 (M+H)+

[0585] ’H NMR (CDCI3, 400 MHz) 5 = 15.32 (br s, 1H), 9.22 (s, 1H), 8.53 (s, 1H), 8.66 (s, 1H), 8.38 (s, 1H), 8.17-8.15 (d, 1H), 8.09-8.07 (d, 1H), 7.56-7.52 (m, 1 H), 6.23-6.20 (d, 1H), 5.59 (m, 1H), 4.82-4.79 (m, 1H), 4.56-4.53 (m, 1H), 3.63 (m, 1H), 3.58 (s, 1H), 3.41-3.38 (d, 1H), 3.26-3.25 (d, 1H) 2.95-2.91 (m,6H), 2.82-2.56 (m, 3H), 2.39 (s, 3H), 3.24 (d, 1H), 2.06-2.00 (m, 4H), 1.95-1.79 (m, 8H), 1.68-1.66 (d, 1H), 1.52-1.39 (m, 3H), 1.36-1.25 (m, 2H), 1.20-1.19 (d, 4H), 0.96-0.93 (m, 9H), 0.76 (d, 3H), 0.65 (d, 3H), 0.15 (d, 3H).1.6.18. Cpd 057

[0586] Int A-Cpd 057 was synthesized using the procedure described in step i of Cpd 049 synthesis, using Int 19 instead of 6-(methoxycarbonyl)nicotinic acid CAS# 17874-76-9 and purification methods known by the skilled in the art.

[0587] LC-MS: m / z (calcd): 1143.6; m / z (obsd): 1144.2 (M+H)+

[0588] Int B-Cpd 057 was synthesized from Int A-Cpd 057, using the procedure described in step ii of Cpd 049 synthesis and purification methods known by the skilled in the art.

[0589] LC-MS: m / z (calcd): 1059.5; m / z (obsd): 1060.2 (M+H)+1.6.18.3. Step iii: Int C-Cpd 057

[0590] A solution of In B-Cpd 057 (200 mg, 0.189 mmol, 1 eq.) in MeOH (10 mL) was treated with 10% Palladium on carbon (50%wet) CAS# 7440-05-3 (200 mg) and then stirred under hydrogen balloon atmosphere for 5 h. After reaction completion, the reaction was filtered through celite, celite bed was washed with excess of MeOH (50 mL). The combined filtrates were concentrated to yield 180 mg of Int C-Cpd 057 which was used as such in the next step.

[0591] LC-MS: m / z (calcd): 969.5; m / z (obsd): 970.2 (M+H)+1.6.18.4. Step iv: Cpd 057

[0592] Cpd 057 was synthesized from Int C-Cpd 057, using the procedure described in step v of Cpd 049 synthesis. Final purification by Prep HPLC (Column: X-SELECT CSH C18 (19x250mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 13 mL / min; Gradient: (Time / % OF B): 0 / 40,2 / 40,10 / 60,13.8 / 60,13.9 / 98,16.5 / 98,16.6 / 40,22 / 40; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 55 mg of Cpd 057.

[0593] LC-MS: m / z (calcd): 929.5; m / z (obsd): 930.5 (M+H)+

[0594] ’H NMR (CDC13, 400 MHz) 5 = 15.30 (s, 1H), 9.22 (s, 1H), 8.54 (s, 1H), 7.32 (d, 1H), 7.16 (s, 1H), 6.70-6.68 (m, 1H), 6.23 (d, 1H), 4.82-4.62 (m, 1H), 4.52 (d, 1H), 3.48 (m, 1H), 3.35 (m, 1H), 3.25-3.10 (m, 2H), 3.01-2.91 (m, 6H), 2.85-2.59 (m, 3H), 2.37-2.30 (m, 5H), 2.20-1.66 (m, 13H), 1.47-1.39 (m, 3H), 1.35-1.15 (m, 6H), 0.98-0.93 (m, 9H), 0.77-0.62 (m, 6H), 0.12-0.10 (m, 3H).1.6.19. Cpd 0581.6.19.1. Step i: Int A-Cpd 058

[0595] To a stirred solution of 4-(methoxycarbonyl) benzoic acid CAS# 1679-64-7 (354 mg, 1.97 mmol, 4.0 eq.) in DCM (5 mb) was added triethylamine (0.355 mb, 2.46 mmol, 5 eq.) followed by DMAP (120 mg, 0.983 mmol, 2.0 eq.) and pivaloyl chloride CAS# 3282-30-2 (0.242 mb, 1.97 mmol, 4.0 eq.) and the resulting mixture was stirred at RT for 1 h. The reaction mixture was then treated with a solution of Int 11 (500 mg, 0.492 mmol, 1.0 eq) in DCM (5 mb) and stirred at RT for 4 h. After reaction completion, the reaction mixture was diluted with water (150 mb) and extracted with EtOAc (2x150 mb). The combined organic layers were washed with brine solution (100 mb), dried over Na2SC>4 and concentrated. A second batch (same conditions, same amounts) was produced and the combined crudes were purified by column chromatography over silica gel using a gradient of EtOAc (0-70%) in hexane to yield 1 g of Int A-Cpd 058.

[0596] LC-MS: m / z (calcd): 1094.6; m / z (obsd): 1095.3 (M+H)+1.6.19.2. Step ii to v: Cpd 058

[0597] Cpd 058 was then synthesized from Int A-Cpd 058 using the procedures described in steps ii to v of Cpd 049 synthesis. Final purification by Prep HPLC (Column: X-select csh phenyl hexyl (19x250mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 14 mL / min; Gradient: (Time / % OF B): 0 / 50, 5 / 50, 10 / 70, 12.8 / 70, 12.9 / 98, 16 / 98, 16.1 / 50, 19 / 50; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 25 mg of Cpd 058.

[0598] LC-MS: m / z (calcd): 955.5; m / z (obsd): 956.9 (M+H)+

[0599] 1H NMR (CDC13, 400 MHz) 5 = 15.22 (s, 1 H), 9.22 (br s, 1 H), 8.54 (s, 1 H) 8.08 (d, 2 H), 7.85 (d, 2 H), 6.21 (d, 1 H), 6.13-6.05 (m, 1 H), 5.69-5.59 (m, 1H), 4.82 (m, 1 H), 4.56 (m, 1 H), 3.65 (br s, 1 H), 3.59 (s, 2H), 3.52-3.47 (m, 1 H), 3.40 (d, 1 H), 3.25 (m, 1 H), 2.97-2.88 (m, 6 H), 2.72-2.59 (m, 3 H), 2.39 (s, 3 H), 2.30 (d, 2 H), 2.10-1.99 (m, 4 H), 1.92-1.73 (m, 8 H), 1.67 (m, 1 H), 1.50 (br s, 1 H), 1.41 (m, 2 H), 1.31-1.22 (m, 3 H), 1.20 (d, 4 H), 0.97-0.92 (m, 9 H), 0.76 (d, 3 H), 0.65 (d, 3 H), 0.15 (d, 3 H).

[0600] The following esters compounds were synthesized using a similar procedure to that of step i of Cpd 058 and steps ii and v of Cpd 049 by selection of reagents, solvents and purification methods known by the skilled in the art.Acid reagent Starting intermediate Final cpd N-°OH Int 11 Cpd 086 4,5,6,7-tetrahydrobenzo[c]isoxazole-3-carboxylic acid(CAS# 261350-47-4)P'N / —' - ' OH Int 11 Cpd 087 4,5,6,7-tetrahydrobenzo [d] isoxazole-3 -carboxylic acid(CAS# 90005-77-9)1.6.20. Cpd 059 & Cpd 0601.6.20.1. Step i: Int A-Cpd 059 / 060

[0601] To a solution ofRifabutin (10 g, 11.81 mmol, 1.0 eq.) and CSA (3.29 g, 14.17 mmol, 1.2 eq.) in acetone (120 mb) was added 2,2-dimethoxypropane (30 mb, 243.25 mmol, 20.6 eq.), and the resulting mixture was stirred at room temperature for 2 hours. Solid NaHCO3 (3.60 g, 42 mmol, 3.6 eq.) was added,and the mixture was further stirred for 30 minutes at room temperature. Then, the reaction mixture was partitioned between DCM (200 mL) and H2O (200 mL). The aqueous phase was back-extracted with CH2C12 (3 x 100 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-5% MeOH in DCM) to afford Int A-Cpd 059 / 060 (11.2 g, 91%yield).

[0602] LC-MS: m / z (calcd): 886.5; m / z (obsd): 887 (M+H)+1.6.20.2. Step ii: Int B-Cpd 059 / 060

[0603] A mixture of Int A-Cpd 059 / 060 (11.2 g, 12.63 mmol, 1.0 eq.) and potassium carbonate (10.55 g, 75.76 mmol, 6 eq.) in MeOH (130 mL) was stirred at 50 °C for 48 h. The reaction mixture was cooled to room temperature and partitioned between DCM (200 mL) and brine (200 mL). The aqueous phase was back-extracted with DCM (3 x 100 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (silica gel, 0-10% MeOH in DCM) to afford Int B-Cpd 059 / 060 (6.7 g, 53% yield).

[0604] LC-MS: m / z (calcd): 844.5; m / z (obsd): 845 (M+H)+1.6.20.3. Step Hi: Int C-Cpd 059 / 060

[0605] To a stirred solution of Int B-Cpd 059 / 060 (1.69 g, 2.0 mmol, 1 eq.) in DCE (25 mL) was added nicotinic anhydride (0.91 g, 4.0 mmol, 2 eq.) batchwise at 0 °C followed by the dropwise addition of a solution of DMAP (0.12 g, 1.0 mmol, 0.5 eq.) in DCE (5 mL). The resulting mixture was stirred for 2 hours at 0 °C, then stirred for 16 hours at room temperature. The reaction mixture was poured into DCM (100 mL) and saturated aq. NaHCO₃ (100 mL). The organic layers were separated and the aqueous phase was extracted with DCM (2 x 100 mL). The combined organic layers were dried over anhydrous MgSCh. filtered, and concentrated under reduced pressure. The crude residue was purified by reversed phase column chromatography (C18 silica gel; mobile phase, ACN / ELOQO mM NHiHCCh+O.l NH3. H2O); gradient, 0% to 95% in 120 min; flowrate, 50 mL / min; detector, UV 254 nm.) to afford Int C-Cpd 059 / 060 (614 mg, 32% yield).

[0606] LC-MS: m / z (calcd): 949.5; m / z (obsd): 950 (M+H)+1.6.20.4. Step iv: Int D-Cpd 059 / 060

[0607] To a solution of Int C-Cpd 059 / 060 (580 mg, 0.61 mmol, 1.0 eq.) in MeOH (6 mL) was added CSA (284 mg, 1.22 mmol, 2.0 eq.), and the resulting mixture was stirred for 30 minutes at room temperature. The reaction mixture was diluted with DCM (100 mL), and washed with aq. saturated NaHCO₃ (100 mL). The organic layer was dried over anhydrous MgSCL, filtered, and concentrated under reduced pressure. The crude residue was purified by reversed phase column chromatography (Cl 8 silica gel; mobile phase, ACN / H O(10 mM NH4HCO3+O. I NH3. H2O); gradient, 0% to 70% in 70 min; flowrate, 40 mL / min; detector, UV 254 nm.) to afford Int D-Cpd 059 / 060 (379 mg, 68% yield).

[0608] LC-MS: m / z (calcd): 909.5; m / z (obsd): 910 (M+H)+1.6.20.5. Step v: Cpd 059 & Cpd 060

[0609] To a sealed tube were added Int D-Cpd 059 / 060 (100 mg, 0.11 mmol, 1.0 eq.), PtO2(25 mg, 0.11 mmol, 1.0 eq.) and EtOH (5 mL), and the resulting mixture was stirred for 16 hours at 40 °C under hydrogen atmosphere (5 atm). The reaction mixture was cooled and concentrated under reduced pressure. The residue was dissolved in DMSO (5 mL), filtered, and the filtrate was purified by prep-HPLC (Column: XBridge Prep OBD C18, 30x150 mm, 5pm; Mobile Phase A: Water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 59% to 89 % B in 10 min; Wave Length: 254nm / 220nm nm) to afford 13.7 mg of Cpd 059 (first eluting) and 11.6 mg of Cpd 060 (second eluting), respectively.Cpd 059 (first eluting)

[0610] LC-MS: m / z (calcd): 913.5; m / z (obsd): 914.8 (M+H)+

[0611] ’HNMR (CDCls, 400 MHz) 5 = 14.86 (s, 1H), 9.45 (s, 1H), 9.17 (d, 1H), 8.80 (dd, 1H), 8.26 (dt, 1H), 8.09 (s, 1H), 7.41 (dd, 1H), 6.16 (d, 1H), 5.20 - 5.09 (m, 2H), 3.85 (d, 1H), 3.53 (s, 1H), 3.45 (d, 1H), 3.40 (dd, 1H), 3.04 - 3.02 (m, 3H), 2.95 (s, 3H), 2.80 - 2.56 (m, 3H), 2.37 (s, 3H), 2.37 - 2.31 (m, 3H), 2.20 - 1.80 (m, 5H), 1.77 (s, 3H), 1.77 - 1.50 (m, 2H), 1.38 (d, 3H), 1.35 - 1.28 (m, 5H), 0.98 (dd, 9H), 0.89 - 0.83 (m, 1H), 0.76 (d, 3H), 0.64 (d, 3H), 0.01 (d, 3H).Cpd 060 (second eluting)

[0612] LC-MS: m / z (calcd): 913.5; m / z (obsd): 914.8 (M+H)+

[0613] ’H NMR (CDCh, 400 MHz) 5 = 15.24 (s, 1H), 9.25 (s, 1H), 9.18 (s, 1H), 8.79 (dd, 1H), 8.58 (s, 1H), 8.28 (dt, 1H), 7.42 - 7.38 (m, 1H), 6.25 (d, 1H), 4.83 (dd, 1H), 4.56 (d, 1H), 3.58 (s, 1H), 3.49 (d, 1H), 3.41 (d, 1H), 3.25 (dd, 1H), 3.00 - 2.92 (m, 2H), 2.92 (s, 3H), 2.74 - 2.50 (m, 3H), 2.40 - 2.20 (m, 2H), 2.18 - 2.01 (m, 4H), 2.00 - 1.83 (m, 5H), 1.83 (s, 3H), 1.60 - 1.35 (m, 4H), 1.28 - 1.10 (m, 5H), 1.05 -0.80 (m, 10H), 0.79 (d, 3H), 0.68 (d, 3H), 0.17 (d, 3H).

[0614] To a stirred solution of 4-bromopicolinic acid CAS# 30766-03-1 (2.98 g, 14.75 mmol, 5 eq.) and 2-Methyl-6-nitrobenzoic anhydride CAS# 434935-69-0 (5.07 g, 14.75 mmol, 5 eq.) in DCM (40 mb) at RT, was added triethylamine (4.10 mb, 29.5 mmol, 10 eq.) and the resulting mixture was stirred for 30 min. The reaction mixture was then treated with a solution of Int 11 (3.00 g, 2.95 mmol, 1 eq.) in DCM (10 mL) and then with a solution of DMAP (0.72 g, 5.90 mmol, 2 eq.) in DCM (10 mb) (simultaneous addition). The reaction mixture was then stirred for 16 h. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water, brine, dried over Na2SC>4 and concentrated. The crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-3%) in DCM to yield 3.50 g of Int A-Cpd 219.

[0615] LC-MS: m / z (calcd): 1115.5; m / z (obsd): 1116.3 (M+H)+1.6.21.2. Step ii: Int B-Cpd 219

[0616] In a 250 mL steel vessel, a solution of Int A-Cpd 219 (3.0 g, 2.685 mmol, 1 eq.) in MeOH (50 mL) was treated with 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex CAS# 95464-05-4 (219 mg, 0.27 mmol, 0.1 eq.) and DIPEA (2.33 mL, 13.4 mmol, 5 eq.). The vessel was then filled with carbon monoxide (40 Psi), slowly heated to 70 °C and then stirred for 36 h at this temperature. After reaction completion, the reaction mixture was cooled to room temperature and excess CO was released. Mixture was then fdtered and filtrate was concentrated. The crude residue was purified by column chromatography over silica gel using a gradient of MeOH (0-3%) in DCM to yield 600 mg of Int B-Cpd 219

[0617] LC-MS: m / z (calcd): 1011.5; m / z (obsd): 1012.1 (M+H)+1.6.21.3. Cpd 219

[0618] Cpd 219 was then synthesized from Int B-Cpd 219 using the procedures described in steps Hi to v of Cpd 049 synthesis. Final purification by Prep HPLC (Column: Xbridge Prep C18 OBD (19x150mm, 5μm); Mobile phase A: lOmM Ammonium bicarbonate in Water; Mobile phase B: Acetonitrile; Flow rate: 13 mL / min; Gradient: (Time / % OF B): 0 / 60, 2 / 60, 10 / 80, 14 / 80, 14.1 / 99, 18 / 99, 18.1 / 60, 22 / 60; Temperature: Ambient). Pure fractions was concentrated under reduced pressure and lyophilized to yield 28 mg of Cpd 219.

[0619] LC-MS: m / z (calcd): 956.5; m / z (obsd): 957.5 (M+H)+

[0620] 1H NMR (CDC13, 400 MHz) 5 = 15.20 (s, 1H), 9.27 (s, 1H), 8.90 (d, 1H), 8.46 (s, 1H), 8.37 (s, 1H), 7.87-7.85 (m, 1H), 6.30 (br s, 1H), 6.21 (d, 1H), 5.78-5.74 (m, 1H), 4.94 (m, 1H), 4.78 (d, 1H), 3.53 (s, 1H), 3.43-3.36 (m, 2H), 3.32 (m, 1H), 3.03 (m, 1H), 2.97-2.90 (m, 5H), 2.72-2.61 (m, 4H), 2.40 (s, 3H), 2.29 (d, 2H), 2.10 (br s, 4H), 1.91-1.80 (m, 4H), 1.74-1.69 (m, 5H), 1.44-1.37 (m, 3H), 1.26 (s, 2H), 1.20 (d, 3H), 1.15 (s, 1H), 0.95 (d, 6H), 0.77 (d, 3H), 0.67 (d, 3H), 0.12 (d, 3H), 0.07 (m, 1H).Table II. Illustrative compoundsstereochemistry arbitrarily assigned defines a stereo isomer wherein isomers have been separated and the stereochemistry for thebond has not been assigned.LC-MS m / z m / zCpd# Structure Method; r.t. (min);(calcd) (obsd)purity (%)0HN^O _A °Cho>pdo935.5 936.8 B; 3.23; 99.8 001 \ T I TAIsomer 1 - Stereochemistry arbitrarily assignedo-^L _ N^Oo^^x / xA / v>0,,. OH OH O^ Jx,,J OH O |Cpd V X^AXAX^NH921.5 922.6 B; 2.81; 96.5 002 \ X I I\ o / / xy\NHIsomer 1 - Stereochemistry arbitrarily assignedo-^L _ N^Oo^^x / xA / x / Oz,OH°H°xXxJ OH O |Cpd V \AXAX^NH921.5 922.7 B; 3.61; 98.6 003 \ XXA\ o / / xy\NHIsomer 2 - Stereochemistry arbitrarily assignedLC-MS m / z m / zCpd# Structure Method; r.t. (min);(calcd) (obsd)purity (%)Cpd1002.6 1003.8 B; 3.26; 100 004 sp' °' \ o / > LO. " ' / '•-..C "1) o.—° >< < ^="H1o zMp O-- Cpd920.5 921.8 B; 2.57; 99.8 005(( P x° —=A / IS / Y. / _° °$ pH5- °.( CZT. x / / '"Ml W.A n. / o ~, / '"M M zJ / Oz.y o— / -X A°O / Oz.—p / \ \Cpd Z". A OHOH6HO0^1z— 'J 988.6 989.9 B; 3.10; 100 006 ^< o=\ XXA\NHZ', X OHOH6HOO^XCpd960.6 961.9 B; 4.19; 99.4 007\ \ XXA NH" K pCpd976.6 977.8 B; 3.24; 97.4 008LC-MS m / z m / zCpd# Structure Method; r.t. (min);(calcd) (obsd)purity (%) / — NCpd AOHOH6HO °^A962.6 963.8 B; 3.55; 99 009 \ \ O L / XM A\NH•H 'Cpd1016.6 1017.9 B; 3.28; 98.6 010 / / ( 1 °='"''\( A AAA i ^° JALA<y i°z-=° AJA^ / \_Ps / / ^_V / Zi / n / V_ / O°° "C=" °On iiln xt / 'i ( ' on unn x $ M of. / x / / ,l'i'8- M Ml-’ UAH°...A / A / A / □o iz o i - °°°zvA vC) \ \xCpd974.6 975.9 B; 3.67; 97.8 Oilo^, CCpd1016.6 1017.8 B; 2.78; 96.3 0129 -N^Q _Cpd -°'-A 975.6 976.8 B; 3.66; 100 013 j \nnNH\ \ AAA NH°HLC-MS m / z m / zCpd# Structure Method; r.t. (min);(calcd) (obsd)purity (%)-°"-A °VHO °Y^Cpd933.5 934.7 B; 3.22; 99.9 014 \ XXXkS-N-y>°Ov>x^x^>xs_ / xC z°'- AOHOH°HOpd °Y^J. x J^ JJ^NH 933.5 934.7 B; 3.14; 99.9 015 \ \ O XZ / xXX^X\ NH1k^-N^OCpd / °" -AOHOH°HO °<rXJ. -X^X JLX-NH 962.6 963.8 B; 2.93; 94.5 016 \ \ o X' yXTXt NH^xx ^N 1^O°X / X / \ / \ / \V^Oz, J-., OH OH O^^ Jxx'■< '' OH o yCpd J x^X xA^NH988.6 989.9 B; 4.50; 97.4 017 \ \ O X / XTX / X\X\ NH°nNf>H HO','X'JOVX^Y^XXS^^-°'X--OHOH°HO °Y^Cpd J \x^X^Xx-NH949.5 950.9 B; 2.54; 98.6 018 \ \ O X / rXyX^ NHN^ _LC-MS m / z m / zCpd# Structure Method; r.t. (min);(calcd) (obsd)purity (%)k^N^OCpd A019 J \OAHOHx5kHOk °^, NH 997.6 998.9 B; 3.21; 94.5 \ XXXN^ _-V XH^Y HN^ JNY O^°^ =x^A^xk^x' ' JO,, J-.C ' J ■<, •' OHp ^ OH OH O^ A.od \ kx-kk / NH990.6 991.9 B; 2.80; 100 020 \ \ OZX / X / ^X\ NHo^^" V-N^OOx^A^^A^Jx^ / x, O,, A, OH OH O'.. XCpd '< '' OH OJ. \A^k / NH961.5 962.9 B; 3.38; 95.6 021 \ \ XXX NH°HN^5H / ''••y. N^ONH2 / ^. OZ,'-S J' -.,; OH OH OH O O^ J\Cpd J. X^jkxkk ^NH976.6 977.8 B; 3.26; 99.8 022 \ XXX°n “5N^ _LC-MS m / z m / zCpd# Structure Method; r.t. (min);(calcd) (obsd)purity (%) < X N <7 o k ^, N_. O ■ / °'- AOHOH°HO °^ACpd J. \ U\JLX. NH1025.6 1026.8 A; 2.08; 95.2 023 \ \ O / XXYXXX^X\ NHIsomer 1 - Stereochemistry arbitrarily assigned9HN^O _o^ / v / x / x / x-° "• AOHOH°HO °Y^Cpd J NH 928.5 929.7 A; 2.33; 95.2 024\ XXX\ oVY NHN^ _Isomer 1 - Stereochemistry arbitrarily assigned9HN^O _o^ / x / x...

Claims

CLAIMS1. A compound, or a pharmaceutically acceptable salt, or solvate, or the salt of a solvate thereof, according to Formula I:IWhereinX is absent, O, or -NR2-;Li is absent, or C1-4 alkylene;R1isphenyl optionally substituted with one or more independently selected R3,5-6 membered monocyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3, where the N heteroatoms may optionally be oxidized;8-10 membered fused bicyclic heteroaryl comprising one or more independently selected N, O, or S heteroatoms, optionally substituted with one or more independently selected R3;3-7 membered monocyclic cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally substituted with one or more groups independently selected from =0 and R3;4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R3, or5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, optionally substituted with one or more groups independently selected from =0 and R3;C1-4 alkyl optionally substituted with one or more groups independently selected from =0 and R3a; R2is H, C1-4 alkyl, or C3-5 monocyclic cycloalkyl;Cy is4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one or more independently selected R4groups,5-10 membered bicyclic bridged, fused, or spiro heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl substituted with one or more independently selected R4group,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected R4, or5-10 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more independently selected R4; Each R3and R3ais independently selected from:halo,CN, or- -YA-LA-R5;Each R4is independently selected from:halo,- =0,CN, or- -YB-LB-R6;Each YA and YB is independently selected from:absent,Ci-4 alkylene optionally substituted with one or more independently selected halo,or 3-7-membered cycloalkyl optionally substituted with one or more independently selected halo; Each LA and LB is independently selected from:absent,- -O-,- -(C=O),- -C(=O)O-,- -C(=NH)NR7a-,- -C(=O)NR7a-,- -C(=O)NR7a-C(=O)-,- -S(=O)-,- -S(=O)2-,- -S(=O)2NR7b-,- -NR7fS(=O)2-,- -NR7CC(=O)-,- -P(=O)R7d-,- -NR7e-,- -P(=O)(OR7d)O-,- -C(=O)NR7fS(=O)2-,- -C(=O)NR7f-O-,- -C(=O)-C(=O)NR7f-,- -OC(=O)-NR7b-,- -OC(=O)-,- -S(=O)(=NR7b)-,- -OP(=O)(OR7d)O-,- -NR7CC(=O)O-,Each R5, R6, R7a, R7b, R7c, R7d, R7eand R7fis independently selected from:- H,Ci-4 alkyl optionally substituted with one or more independently selected halo, OH, phenyl, pyridinyl, deuterium, -C(=0)NHCH3, -NHC(=O) CH3, or cyclopropyl,3-7 membered monocyclic cycloalkyl optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,3-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, phenyl, pyridinyl, C1-4 alkyl optionally substituted with one or more independently selected halo, - S(=O)2-cyclopropyl, -C(=O)OCH3, -S(=O)2CH3, -C(=O)-cyclopropyl, -P(=O)(CH3)2, -C(=0)0H, -N(CH3)2, CN, -C(=0)NHCH3, -NHC(=0)-CH3, -C(=0)NH2, or C1-4 alkoxy optionally substituted with one or more independently selected halo,6-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P, Se, Si, B, or S heteroatoms, optionally substituted with one or more independently selected halo, OH, =0, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,phenyl, optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo,5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected halo, OH, -C(=0)NH2, -C(=0)NHCH3, C1-4 alkyl optionally substituted with one or more independently selected halo, or C1-4 alkoxy optionally substituted with one or more independently selected halo; where the N heteroatoms of said heteroaryl may optionally be oxidized.. A compound or a pharmaceutical acceptable salt according to claim 1, wherein Cy is 4-7 membered monocyclic heterocycloalkyl comprising one or more independently selected N, O, P or S heteroatoms, which heterocycloalkyl is substituted with one R4group.

3. A compound or a pharmaceutical acceptable salt according to claim 2, wherein R4is -CH2CH2CH3.-CH2CH(CH3)2, -CH2-Cyclopropyl -CH2CH2CH2OH, -CH2CH(CH3)CH2OH, -CH2C(=O)NH2, - CH2CH2CH2C(=O)NH2, or -CH2CH(CH3)CH2C(=O)NH2.

4. A compound or a pharmaceutical acceptable salt according to claim 1, wherein the compound of the invention is according to Formula II:4 \ / H° OH% °''•», / I H NHUNHN— Z—.

5. A compound or a pharmaceutical acceptable salt according to any one of claims 1-4, wherein X is absent, or X is -NR2-, and R2is H.

6. A compound or a pharmaceutical acceptable salt according to any one of claims 1-5, wherein Li is absent.

7. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is phenyl substituted with one, two or three independently selected R3.

8. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is pyrazolyl, thiazolyl, oxazolyl, triazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiadiazolyl, imidazolyl, triazolopyridinyl, tetrahydrobenzoisoxazolyl, or pyrazolopyrimidinyl, each of which is optionally substituted with one, two or three independently selected R3, where the N heteroatoms may optionally be oxidized.

9. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [l.l.l]pentanyl, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, or bicyclo[2.2.2]octanyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R3.

10. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, thiomorpholinyl, or azaphosphinanyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R3.

11. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is 2-oxa-5-azabicyclo[2.2.1]heptanyl, diazepanyl, 7-oxa-2-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 8-oxa-2-azaspiro[4.5]decanyl, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro- 1H-furo[3,4-c]pyrrolyl, 3,9-diazaspiro[5.5]undecanyl, 2-azaspiro[3.3]heptanyl, 2,8- diazaspiro[4.5]decanyl, 1,8-diazaspiro[4.5]decanyl, 1,3,8-triazaspiro[4.5]decanyl, 4, 5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridinyl, or 2-oxaspiro[3.3]heptanyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R3.

12. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1is Ci-4 alkyl substituted with one, two or three groups independently selected from =0 and R3a.

13. A compound or a pharmaceutical acceptable salt according to any one of claims 1-6, wherein R1iswherein * represents the points of attachment.

14. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-13 and pharmaceutically acceptable excipients.

15. A pharmaceutical composition according to claim 14, comprising a further therapeutical agent.

16. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-13, or a pharmaceutical composition according to claim 14 or 15 for use in medicine.

17. A compound or a pharmaceutically acceptable salt thereof, according to any one of claims 1-13, or a pharmaceutical composition according to claim 14 or 15 for use in the prevention and or treatment of tuberculosis, and / or non-tuberculous mycobacteria diseases.

18. A pharmaceutical composition according to claim 15, wherein the further therapeutical agent is an agent for the prevention and or treatment of tuberculosis, and / or non-tuberculous mycobacteria diseases.

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