WO2018023081A1 - 6-phenylpyrido[2,3-d]pyrimidine compounds as antibacterial agents - Google Patents

Abstract

The disclosure relates to antibacterial compounds having the Formula (I), where R1, R2, R3, R4, R8, n, and p are described herein, as well as stereoisomers, pharmaceutically acceptable salts, esters, and prodrugs thereof, pharmaceutical compositions comprising such compounds, methods of treating bacterial infections by the administration of such compounds, and processes for the preparation of the compounds.

Description

6-PHEN YLP YRID O [2,3-D] P YRIMIDINE COMPOUNDS AS ANTIBACTERIAL

AGENTS

Government Support

[0001] The work described herein was supported by the National Institute of Allergy And Infectious Diseases of the National Institutes of Health under Award Number R21 All 13572. The U.S. Government has certain rights to the claimed invention.

Cross Reference to Related Applications

[0002] This application claims the benefit of U.S. Provisional Application No. 62/368,331, filed July 29, 2016, the content of which is incorporated herein by reference in its entirety.

Field of Disclosure

[0003] This disclosure pertains generally to treating infections caused by bacteria. More specifically, the present disclosure pertains to treating bacterial infections by modulating activity of the biotin carboxylase component (AccC) of bacterial acetyl coenzyme- A carboxylase (ACCase). The present disclosure provides small molecule inhibitors of AccC, pharmaceutical formulations containing such inhibitors, methods of treating patients with such pharmaceutical formulations, and methods of preparing such pharmaceutical formulations and inhibitors. The present disclosure pertains to treating bacterial infections by administering compounds capable of inhibiting activity of AccC, either alone or in combination with administering a second antibacterial compound.

Background of the Disclosure

[0004] Over the past several decades, the frequency of antimicrobial resistance and its association with serious infectious diseases have increased at alarming rates. The problem of antibacterial resistance is compounded by the existence of bacterial strains resistant to multiple antibacterials. Thus, there is a need for new antibacterials, particularly antibacterials with novel mechanisms of action.

[0005] A previously unexploited but highly conserved target, AccC, provides a new opportunity for developing broad-spectrum antibacterial small molecules that comprise a new class of active bactericidal chemical entities that should encounter little, if any, naturally- occurring, target-related resistance. AccC is part of multiple-component acetyl coenzyme-A carboxylase (ACCase) component of bacterial acetyl coenzyme-A carboxylase (ACCase)).

AccC is present across all bacterial species of interest and is involved in the first committed step in fatty acid biosynthesis (Cheng et al., Bioorg. Med. Chem. Lett., 2009, 19, 6507-6514; Miller et al., Proc. Natl. Acad. Sci. USA, 2009, 106(6), 1737-1742; Freiberg et al., J. Biol. Chem., 2004, 279(25), 26066-26073; Fawaz et al., Bioorg. Chem., 2011, 39, 185-191; and Tong et al., J. Cell. Biochem., 2006, 99, 1476-1488). Thus, AccC is essential for bacterial survival and presents an ideal target for antibiotic activity in a wide range of bacterial species.

[0006] Inhibition of AccC with small molecule inhibitors therefore has the potential to provide treatment for a broad spectrum of bacterial infections. For this reason, there remains a considerable need for novel and potent small molecule inhibitors of AccC.

Summary of the Disclosure

[0007] A first aspect of the disclosure relates to compounds of Formula (I):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof,

wherein:

R1 is (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R6;

R₂ is H, (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5', aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7; R3 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -OH, -NH2, (C1-C4) alkylamino, or (C1-C4) dialkylamino;

or R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring; or R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form a heteroaryl ring;

R₄ is a heterocycloalkyl ring;

R5 is (C1-C6) alkyl, -(CH₂)m(C3-C7) cycloalkyl, or -(CH₂)mheterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

R5' is (C1-C6) alkyl, -(CH2)o(C3-C7) cycloalkyl, or -(CH₂)₀heterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and

-C(0)0(C1-C4) alkyl;

each Rs is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -NH₂, (C1-C4) alkylamino, (C1-C4) dialkylamino, or -N(H)S(0)_q (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R7 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -NH₂, (C1-C4) alkylamino, (C1-C4) dialkylamino, or -N(H)S(0)_q (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R8 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -OH, -CN, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13, -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

or two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9; or two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9; or two R8 on the same carbon atom together form a (C3-C7) spirocycloalkyl ring, wherein the spirocycloalkyl ring is optionally substituted with one or more R9; or two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the

spiroheterocycloalkyl ring is optionally substituted with one or more R9;

each R9 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, -OH, halogen, -CN, -NH₂, (C1-C4) alkylamino, or (C1-C4) dialkylamino;

each R1o and R11 is independently H, (C1-C4) alkyl, (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C6) cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH; or

R10 and R11 together with the nitrogen atom to which they are attached form a

heterocycloalkyl ring optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, -OH, halogen, -NH2, (C1-C4) alkylamino, and (C1-C4) dialkylamino;

each R12 and R13 is independently H, (C1-C4) alkyl, or (C3-C7) cycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from CN, -NH₂, -OH, and halogen;

q is 1 or 2; and

each m, n, o, and p is independently 0, 1, 2, or 3.

[0008] Another aspect of the disclosure relates to a method of treating a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0009] Another aspect of the disclosure relates to a method of preventing a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0010] Another aspect of the disclosure relates to a method of reducing the risk of a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0011] Another aspect of the disclosure is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0012] Another aspect of the present disclosure relates to a method of treating a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0013] Another aspect of the present disclosure relates to a method of preventing a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0014] Another aspect of the present disclosure relates to a method of reducing the risk of a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0015] Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a bacterial infection.

[0016] Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the prevention of a bacterial infection. [0017] Another aspect of the present disclosure relates to the use of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the reduction of the risk of a bacterial infection.

[0018] Another aspect of the present disclosure relates to a pharmaceutical composition or formulation comprising an effective amount of an antibacterial compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier or diluent.

[0019] Another aspect of the present disclosure relates to a method of inhibiting a carboxylase enzyme in gram-negative bacteria, thereby affecting bacterial growth, comprising administering to a patient in need of such inhibition an AccC-inhibitory compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0020] Another aspect of the present disclosure relates to a method of inhibiting a carboxylase enzyme in gram-positive bacteria, thereby affecting bacterial growth, comprising administering to a patient in need of such inhibition an AccC-inhibitory compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0021] Another aspect of the present disclosure relates to a method of inhibiting AccC, thereby modulating the virulence of a bacterial infection, comprising administering to a patient in need of such inhibition an AccC-inhibitory compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0022] Another aspect of the present disclosure relates to a method for treating a patient having a bacterial infection comprising administering to the patient in need thereof an antibacterially effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In a more specific embodiment of the method of treatment, the bacterial infection is a gram-negative bacterial infection. In a further specific embodiment the patient is a mammal and in certain embodiments, a human.

[0023] Another aspect of the present disclosure relates to a method for treating a patient having a bacterial infection comprising administering to the patient in need thereof an antibacterially effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In a more specific embodiment of the method of treatment, the bacterial infection is a gram-positive bacterial infection. In a further specific embodiment the patient is a mammal and in certain embodiments, a human.

[0024] Another aspect of the present disclosure relates to a method of administering an antibacterially effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with a fermentative or non-fermentative gram-negative bacteria. Examples of such bacteria include Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Franciscellaceae (e.g., Franciscella tularensis) and Neisseria species.

[0025] Another aspect of the present disclosure relates to a method of administering an antibacterially effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with gram- negative bacteria. Examples of such bacteria include, but are not limited to, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Acinetobacter, Burkholderia cepacia, Alcaligenes xylosoxidans, Haemophilus, Franciscellaceae, a Neisseria species, Enterobacteriaceae, such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Yersinia (e.g., Yersinia pestis), Morganella, Cedecea, Edwardsiella species and Escherichia coli. In one embodiment, the gram negative bacteria is Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Franciscellaceae or a Neisseria species.

[0026] Another aspect of the present disclosure relates to a method of administering an antibacterially effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with gram- positive bacteria. Examples of such bacteria include Staphylococcus, Streptococcus,

Enter ococcus, Bacillus, Clostridium, Mycobacterium, and Listeria species.

[0027] The present disclosure further provides methods of treating, preventing, or reducing the risk of a bacterial infection associated with modulation of AccC comprising administering to a subject a compound of the disclosure, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0028] The present disclosure provides inhibitors of AccC that are therapeutic agents in the treatment of bacterial infections, including, but not limited to, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans,

Enter obacteriaceae, Haemophilus, Acinetobacter, Mycobacterium, Franciscellaceae, a Neisseria species, Staphylococcus, Streptococcus, Enterococcus, Bacillus, Clostridium and Listeria species. Ultimately, the present disclosure provides the medical community with a novel compounds and pharmacological strategy for the treatment of bacterial infections by targeting AccC enzymes.

Detailed Description of the Disclosure

[0029] The present disclosure provides novel compounds and compositions capable of inhibiting the activity of AccC. The disclosure features methods of treating, preventing, or reducing the risk of a bacterial infection in which AccC plays a role by administering to a patient in need thereof a therapeutically effective amount of a compound of the Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. The methods of the present disclosure can be used in the treatment of a variety of bacterial infections including, but not limited to, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Franciscellaceae, a Neisseria species, Staphylococcus, Streptococcus, Enterococcus, Bacillus, Clostridium, Mycobacterium, Acinetobacter, and Listeria species.

[0030] In a first aspect of the disclosure, the compounds of Formula (I) are described:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof, wherein R1, R_, R3, R4, R8, n, and p are as described herein above.

[0031] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited in this specification are incorporated herein by reference in their entireties.

Definitions

[0032] The articles "a" and "an" are used in this disclosure to refer to one or more than one (e.g., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.

[0033] The term "and/or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0034] Unless specifically stated, as used herein, the term "about" refers to a range of values ± 10% of a specified value. For example, the phrase "about 200" includes ± 10% of 200, or from 180 to 220. When stated otherwise the term about will refer to a range of values that include ± 20%, ± 10%, or ± 5%, etc. [0035] The term "optionally substituted" is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (e.g., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus the term "optionally substituted" means that a given chemical moiety has the potential to contain other functional groups, but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxide, -(C=0), -OH, -CN, -COOH, -CH₂CN, -0-(C1-C6) alkyl, (C1-C6) alkyl, (C1-C6) alkoxy, (C1-C6) haloalkyl, (C1-C6) haloalkoxy, -0-(C₂-C6) alkenyl, -0-(C2-C6) alkynyl, (C2-C6) alkenyl, (C₂-C6) alkynyl, -OH, -OP(0)(OH)₂, -OC(0)(C1-C6) alkyl, -C(0)(C1-C6) alkyl,

-OC(0)0(C1-C6) alkyl, -NH₂, -NH((C1-C6) alkyl), -N((C1-C6) alkyl)₂, -NHC(0)(C1-C6) alkyl, -C(0)NH(C1-C6) alkyl, -S(0)₂(C1-C6) alkyl, -S(0)NH(C1-C6) alkyl, and S(0)N((C1-C6) alkyl)₂. The substituents can themselves be optionally substituted. "Optionally substituted" as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0036] As used herein, the term "substituted" means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0037] As used herein, the term "unsubstituted" means that the specified group bears no substituents.

[0038] Unless otherwise specifically defined, the term "aryl" refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(C1-C6) alkyl, (C1-C6) alkyl, -0-(C₂-C6) alkenyl, -0-(C₂-C6) alkynyl, (C₂-C6) alkenyl, (C₂-C6) alkynyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C₄) haloalkoxy, -OH,

-OP(0)(OH)₂, -OC(0)(C1-C6) alkyl, -C(0)(C1-C6) alkyl, -OC(0)0(C1-C6) alkyl, -NH>,

-NH((C1-C6) alkyl), N((C1-C6) alkyl)₂, -S(0)₂-(C1-C6) alkyl, -S(0)NH(C1-C6) alkyl, and

-S(0)N((C1-C6) alkyl)₂. The substituents can themselves be optionally substituted. Furthermore when containing two fused rings the aryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0039] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic aromatic radical of 5 to 24 ring atoms or a polycyclic aromatic radical, containing one or more ring heteroatoms selected from N, O, and S, the remaining ring atoms being C. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, and S. The aromatic radical is optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,

benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3- c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine,

dihydrobenzoxanyl, quinolinyl, isoquinolinyl, 1 ,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l ,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l ,5-a]pyridinyl, [1 ,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro-2H-l ²-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4] thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5- naphthyridinyl, furo[3,2-b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo [l,2,3]triazolyl, imidazo[l,2-a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l ,2,5]oxadiazole, l,3-dihydro-2H-benzo[d]imidazol-2-one, 3,4-dihydro-2H-pyrazolo [l,5-b][l,2]oxazinyl, 4,5,6, 7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore when containing two fused rings the heteroaryl groups herein defined may have an unsaturated or partially saturated ring fused with a fully saturated ring. Exemplary ring systems of these heteroaryl groups include indolinyl, indolinonyl, dihydrobenzothiophenyl,

dihydrobenzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, 3,4- dihydro-lH-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl, and dihydrobenzoxanyl.

[0040] Halogen or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0041] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (C1 -C4) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, and tert-butyl.

[0042] "Alkoxy" refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms containing a terminal "O" in the chain, e.g., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0043] "Cycloalkyl" or "carbocyclyl" means monocyclic or polycyclic saturated carbon rings containing 3-18 carbon atoms. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl and derivatives thereof. A C3-C8 cycloalkyl is a cycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkyl group can be fused (e.g., decalin) or bridged (e.g., norbornane).

[0044] "Heterocyclyl" or "heterocycloalkyl" refer to monocyclic or polycyclic rings containing carbon and heteroatoms taken from oxygen, nitrogen, or sulfur and wherein there is not delocalized π electrons (aromaticity) shared among the ring carbon or heteroatoms. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetadinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl. [0045] The term "hydroxyalkyl" means an alkyl group as defined above, where the alkyl group is substituted with one or more OH groups. Examples of hydroxyalky 1 groups include HO-CH₂-, HO-CH₂-CH₂- and CH₃-CH(OH)-.

[0046] The term "haloalkyl" as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0047] The term "haloalkoxy" as used herein refers to an alkoxy group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0048] The term "cyano" as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C≡N.

[0049] The term "oxide" as used herein refers to a "-0 ©" group on a heteroatom atom (e.g., N-oxide (-N-O©) or S-oxide (-S-O©)).

[0050] "Spirocycloalkyl" or "spirocyclyl" means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can further be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g., O, N, S, or P). A (C₃- C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.

[0051] The term "spiroheterocycloalkyl" or "spiroheterocyclyl" is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0052] The term "alkylamino" as used herein refers to an amino or NH2 group where one of the hydrogens have been replaced with an alkyl group, as defined herein above, e.g., -NH(alkyl). Example of alkylamino groups include, but are not limited to, methylamino (e.g., -NH(CH₃)), ethylamino, propylamino, iso-propylamino, n-butylamino, sec-butylamino, tert-butylamino, etc. [0053] The term "dialkylamino" as used herein refers to an amino or NHa group where both of the hydrogens have been replaced with alkyl groups, as defined herein above, e.g., -N(alkyl)₂. The alkyl groups on the amino group can be the same or different alkyl groups. Example of alkylamino groups include, but are not limited to, dimethylamino {e.g., -N(CH2)2), diethylamino, dipropylamino, diiso-propylamino, di-n-butylamino, di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino, methyl(butylamino), etc.

[0054] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0055] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0056] The disclosure also includes pharmaceutical compositions comprising an effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1 ,1-methene-bis- 2-hydroxy-3-naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0057] A "patient" or "subject" is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.

[0058] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

[0059] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a

pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0060] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0061] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0062] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0063] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0064] The term "hydrate," refers to a combination of water with a compound of formula (I) or (Π) wherein the water retains its molecular state as water and is either absorbed, adsorbed or contained within a crystal lattice of the substrate molecule. [0065] The term "antibacterial agent" refers to agents that have either bactericidal or bacteriostatic activity. The term "inhibiting the growth" indicates that the rate of increase in the numbers of a population of a particular bacterium is reduced. Thus, the term includes situations in which the bacterial population increases but at a reduced rate, as well as situations where the growth of the population is stopped, as well as situations where the numbers of the bacteria in the population are reduced or the population even eliminated. If an enzyme activity assay is used to screen for inhibitors, one can make modifications in uptake/efflux, solubility, half-life, etc. to compounds in order to correlate enzyme inhibition with growth inhibition. The activity of antibacterial agents is not necessarily limited to bacteria but may also encompass activity against parasites, virus, and fungi.

[0066] The present disclosure relates to compounds or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, capable of inhibiting AccC, which are useful for the treatment of bacterial infections. The disclosure further relates to compounds, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, which are useful for inhibiting AccC.

[0067] In one embodiment, the compounds of Formula (I) have the structure of Formula (la):

(la),

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0068] In another embodiment, the compounds of Formula (I) have the structure of Formula 0b):

(lb), and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0069] In another embodiment, the compounds of Formula (I) have the structure of Formula (Ic):

(Ic),

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

In another embodiment, the compounds of Formula (I) have the structure of Formula R₃)_n

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0071] In still another embodiment of Formula (I), R₄ is pyrrolidinyl substituted with at least two R8 on adjacent atoms, the two R8 on adjacent atoms together with those atoms form a cyclopropyl substituted with R9, and the compounds of Formula (I) have the structure of Formula (Id-X):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0072] In one embodiment, the compounds of Formula (I) have the structure of Formula (Ie) or (If):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0073] In another embodiment of Formula (I), PU is pyrrolidinyl substituted with at least two R8 on adjacent atoms, the two R8 on adjacent atoms together with those form a cyclopropyl substituted with Rs, and the compounds of Formula (I) have the structure of Formula (Ie-X) or (If-X):

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0074] In another embodiment, the compounds of Formula (I) have the structure of Formula (Ig):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0075] In another embodiment, the compounds of Formula (I) have the structure of Formula (Ih):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0076] In another embodiment, the compounds of Formula (I) have the structure of Formula (Ii):

00,

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0077] In still another embodiment of Formula (I), R4 is piperidinyl substituted with at least two R8 on the same carbon atom, the two R8 together with the carbon atom to which they are attached and R₄ form a spiroheterocycloalkyl ring substituted with R and (R8)_P-2, and the compounds of Formula (I) have the structure of Formula (Ii-X):

(Ii-X),

or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof

[0078] In another embodiment, the compounds of Formula (I) have the structure of Formula (Ij):

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, and tautomers thereof.

[0079] In yet another embodiment of Formula (I), FU is piperidinyl substituted with at least two R8 on the same carbon atom, the two R8 together with the carbon atom to which they are attached and R₄ form a spiroheterocycloalkyl ring substituted with R9 and (RS)P-2, and the compounds of Formula (I) have the structure of Formula (Ij-X):

(ij-x), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

[0080] In one embodiment of Formula (I) as described above, n is 0. In certain

embodiments, R2 is hydrogen or halogen. In certain embodiments, R₂ is H, CI, or Br. In some embodiments, R1 is halogen, -OR5, aryl, or heteroaryl, wherein the aryl or heteroaryl is unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C1-C4) alkyl, (C1-C4) alkoxy, and halogen. In some embodiments, R1 is Br, CI, isobutoxy, unsubstituted pyridyl, pyridyl substituted with halogen and (C1-C4) alkoxy, pyridyl substituted with (C1-C4) alkoxy, unsubstituted phenyl, or thiazole substituted with (C1-C4) alkyl. In certain embodiments, R1 is unsubstituted pyridyl, pyridyl substituted with F and methoxy, pyridyl substituted with methoxy, or thiazole substituted with methyl. In still further embodiments, which may be combined with any of the preceding embodiments, R₄ is pyrrolidine. In some embodiments, R₄ is pyrrolidine, p is 1, and R8 is (C1-C4) alkyl substituted with one or more substituents selected from the group consisting of -N R12 R13 and -OH. In certain embodiments, R₄ is pyrrolidine, p is 1, and R8 is (C1-C4) alkyl substituted with -NH2 or OH In some embodiments, R8 is methyl substituted with -OH or -NH2. In other embodiments, R₄ is pyrrolidine, p is 2, the two R8 are on adjacent atoms, and the two R8 together with the atoms to which they are attached form a cyclopropyl ring, wherein the cyclopropyl ring is unsubstituted or substituted with one or more R9. In certain embodiments, the cyclopropyl ring is substituted with -NH2.

[0081] In certain embodiments of Formula (I), two R8 on adjacent atoms together with the atoms to which they are attached form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is unsubstituted or substituted with one or more R9. In other embodiments, two R8 on adjacent atoms together with the atoms to which they are attached form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In still other

embodiments, two R8 on the same carbon atom together with the carbon to which they are attached and the R4 group form a (C3-C7) spirocycloalkyl ring, wherein the spirocycloalkyl ring is optionally substituted with one or more R9. In yet other embodiments, two R8 on the same carbon atom together with the carbon to which they are attached and the C4 group form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0082] In some embodiments of the Formulae above, R1 is (C1-C3) alkyl, (C1-C3) haloalkyl, halogen, -OR5, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R6. In another embodiment, R1 is (C1-C3) alkyl, (C1-C3) haloalkyl, halogen, or -OR5,. In yet another embodiment, R1 is (C1-C3) alkyl, (C1-C3) haloalkyl, or halogen. In another embodiment, R1 is -OR5, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R6. In another embodiment, R1 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R6. In yet another embodiment, R1 is (C1-C3) haloalkyl, halogen, -OR5, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R6. In another embodiment, R1 is (C1-C3) haloalkyl, halogen, -OR5, or aryl optionally substituted with one or more R6. In another embodiment, R1 is (C1-C3) alkyl, halogen, -OR5, or aryl optionally substituted with one or more R6. In yet another embodiment, R1 is halogen, -OR5, or aryl optionally substituted with one or more R6. In another embodiment, R1 is (C1-C3) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6. In yet another embodiment, R1 is (C1-C3) alkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6. In yet another embodiment, R1 is halogen, -OR5, or heteroaryl optionally substituted with one or more R6.

[0083] In some embodiments of the Formulae above, R2 is H, (C1-C3) alkyl, (C1-C3) haloalkyl, halogen, -OR5', aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7. In another embodiment, R2 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, or -OR5'. In yet another embodiment, R2 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen. In another embodiment, R1 is (C1-C4) alkyl, (C1-C4) haloalkyl, or halogen. In another embodiment, R₂ is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7. In yet another embodiment, R₂ is -OR5', aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7. In another embodiment, R₂ is H, (C1-C4) haloalkyl, halogen, -OR5¹, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7. In yet another embodiment, R₂ is (C1-C4) haloalkyl, halogen, -OR5¹, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7. In another embodiment, R₂ is H, (C1-C4) haloalkyl, halogen, -OR5', or aryl optionally substituted with one or more R7. In yet another embodiment, R₂ is H, (C1-C4) haloalkyl, halogen, -OR₅', or heteroaryl optionally substituted with one or more R7. In another embodiment, R2 is (C1-C4) haloalkyl, halogen, -OR5, or aryl optionally substituted with one or more R7. In yet another embodiment, R₂ is (C1-C4) haloalkyl, halogen, -OR5', or heteroaryl optionally substituted with one or more R7. In another embodiment, R2 is H, halogen, -OR5', or aryl optionally substituted with one or more R7. In yet another embodiment, R2 is H, halogen, -OR5¹, or heteroaryl optionally substituted with one or more R7. In another

embodiment, R2 is halogen, -OR7', or aryl optionally substituted with one or more R7. In yet another embodiment, R2 is halogen, -OR5', or heteroaryl optionally substituted with one or more R7. In another embodiment, R2 is H or halogen. In yet another embodiment, R2 is H. In another embodiment, R₂ is halogen.

[0084] In some embodiments of the Formulae above, R3 is (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, -OH, -NH2, (C1-C3) alkylamino, or (C1-C3) dialkylamino. In another embodiment, R3 is (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, or (C1-C3) haloalkoxy. In another embodiment, R3 is (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, or halogen. In another embodiment, R3 is halogen, -OH, -NH2, (C1-C3) alkylamino, or (C1-C3) dialkylamino. In another embodiment, R3 is -OH, -NH2, (C1-C3) alkylamino, or (C1-C3) dialkylamino. In another embodiment, R3 is -OH or -NH2. In another embodiment, R3 is -NH2, (C1-C3) alkylamino, or (C1-C3) dialkylamino. In another embodiment, R.3 is (C1-C3) alkyl, (C1-C3) alkoxy, or halogen. In another embodiment, R3 is (C1-Cs) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, or halogen. In another embodiment, R3 is (C1-C3) haloalkyl, (C1-C3) haloalkoxy or halogen.

[0085] In some embodiments of the Formulae above, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring. In another embodiment, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form a heteroaryl ring.

[0086] In some embodiments of the Formulae above, R₄ is a 5- or 6-membered

heterocycloalkyl ring containing one to three heteroatoms selected from O, N, or S. In another embodiment, R₄ is R₄ is a 5-membered heterocycloalkyl ring containing one to three heteroatoms selected from O, N, or S. In another embodiment, R₄ is a 6-membered heterocycloalkyl ring containing one to three heteroatoms selected from O, N, or S. In another embodiment, R4 is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl. In another embodiment, R₄ is piperidinyl. In another embodiment, R₄ is piperazinyl. In another embodiment, R₄ is pyrrolidinyl. In another embodiment, R₄ is azetadinyl.

[0087] In some embodiments of the Formulae above, R5 is (C1-C5) alkyl, -(CH₂)m(C3-C7) cycloalkyl, or -(CH₂)mheterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R5 is (C1-C5) alkyl, -(CH2)m(C3-C7) cycloalkyl, or -(CH₂)mheterocycloalkyl, wherein the alkyl is optionally substituted with -C(0)OH. In yet another embodiment, R5 is (C1-Cs) alkyl, -(CH₂)_m(C3-C7) cycloalkyl, or -(CH₂)mheterocycloalkyl. In another embodiment,

R5 is (C1-Cs) alkyl optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In yet another embodiment, R5 is (C1-C5) alkyl optionally substituted with -C(0)OH. In another embodiment, R5 is (C1-Cs) alkyl. In yet another embodiment, R5 is -(CH₂)_m(C3-C7) cycloalkyl or -(CH₂)mheterocycloalkyl. In another embodiment, R5 is (C1-Cs) alkyl, -(CH2XC3-C7) cycloalkyl, or -(CH_)heterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In yet another embodiment, R5 is (C1-Cs) alkyl, -(CH>)(C3-C7) cycloalkyl, or -(CH2)heterocycloalkyl, wherein the alkyl is optionally substituted with C(0)OH.

[0088] In some embodiments of the Formulae above, R5' is (C1-Cs) alkyl, -(CH2)_m(C3-C7) cycloalkyl, or -(CH2)mheterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R5' is (C1-Cs) alkyl, -(CH₂)m(C3-C7) cycloalkyl, or -(CH₂)mheterocycloalkyl, wherein the alkyl is optionally substituted with -C(0)OH. In yet another embodiment, R5¹ is (C1-Cs) alkyl, -(CH₂)_m(C3-C7) cycloalkyl, or -(CH^mheterocycloalkyl. In another embodiment,

R5' is (C1-Cs) alkyl optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In yet another embodiment, R5¹ is (C1-C5) alkyl optionally substituted with -C(0)OH. In another embodiment, R5' is (C1-C5) alkyl. In yet another embodiment, R5' is -(CH2)m(C3-C7) cycloalkyl or -(CH^mheterocycloalkyl. In another embodiment, R5¹ is (C1-Cs) alkyl, -(CH₂)(C3-C7) cycloalkyl, or -(CH₂)heterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In yet another embodiment, R5' is (C1-Cs) alkyl, -(CH2XC3-C7) cycloalkyl, or -(CH₂)heterocycloalkyl, wherein the alkyl is optionally substituted with C(0)OH.

[0089] In some embodiments of the Formulae above, R6 is (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, -NH2, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R6 is (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, or (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and

-C(0)0(C1-C4) alkyl. In another embodiment, R6 is (C1-C₃) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, or (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R6 is halogen, -NH2, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl. In another embodiment, R6 is -NH₂, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl. In another embodiment, R6 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, -NH2, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl.

[0090] In another embodiment, R6 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, -NH2, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH. In another embodiment, R6 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R6 is (C1-C3) alkyl, (d-Cs) alkoxy, halogen, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH. In another embodiment, R6 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, -NH2, (C1-C3) alkylamino, (d-Cs) dialkylamino, or

-N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R6 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH.

[0091] In some embodiments of the Formulae above, R7 is (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, -NH2, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R7 is (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, halogen, or (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and

-C(0)0(C1-C4) alkyl. In another embodiment, R7 is (C1-C₃) haloalkyl, (C1-C3) alkoxy, (C1-C3) haloalkoxy, or (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R7 is halogen, -Nth, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl. In another embodiment, R7 is -NH₂, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl. In another embodiment, R7 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, -Nth, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl.

[0092] In another embodiment, R7 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, -NH2, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH. In another embodiment, R7 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, (C1-C3) alkylamino, (C1-C?) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R7 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, (C1-C3) alkylamino, (C1-C3) dialkylamino, or -N(H)S(0)q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH. In another embodiment, R7 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, -NH2, (C1-C3) alkylamino, (C1-C3) dialkylamino, or

-N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R7 is (C1-C3) alkyl, (C1-C3) alkoxy, halogen, (C1-C3) dialkylamino, or -N(H)S(0)_q (C1-C3) alkyl, wherein the (C1-C3) alkyl is optionally substituted with one or more substituents selected from -C(0)OH.

[0093] In some embodiments of the Formulae above, R8 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -OH, -CN, -NR10R11, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13, -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R8 is (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen or (C1-C4) alkyl optionally substituted with one or more substituents selected from -NR12R13, -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In yet another embodiment, R8 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, or (C1-C4) haloalkoxy. In another embodiment, R8 is halogen, -OH, -CN, -NR1oR1i, -C(0)NH₂, or oxide. In yet another embodiment, R8 is -OH, -CN, -NR1oR1i, -C(0)NH₂, or oxide. In another embodiment, R8 is (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13, -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl. In yet another embodiment, R8 is (C1-C4) alkyl, halogen, -OH, -NR1oR11, -C(0)NH_, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R1₃, -OH, and -C(0)0(C1-C4) alkyl. In another embodiment, R8 is (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R₁₃ and -OH.

[0094] In some embodiments of the Formulae above, two R8 on adjacent atoms together form a (C₃-C7) cycloalkyl ring optionally substituted with one or more R9. In another embodiment, two R8 on adjacent atoms together form a heterocycloalkyl ring optionally substituted with one or more Rs. In yet another embodiment, two R8 on the same carbon atom together form a (C₃-C7) spirocycloalkyl ring optionally substituted with one or more R9. In yet another embodiment, two R8 on the same carbon atom together form a spiroheterocycloalkyl ring optionally substituted with one or more R9.

[0095] In some embodiments of the Formulae above, R9 is (C1-C₃) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C₃) haloalkoxy, (C1-C3) hydroxyalkyl, -OH, halogen, -CN, -NH2, (C1-C₃) alkylamino, or (C1-C₃) dialkylamino. In another embodiment, R9 is (d-C₃) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C₃) haloalkoxy, or (C1-C3) hydroxyalkyl. In yet another embodiment, R9 is -OH, halogen, -CN, -NH2, (C1-C3) alkylamino, or (C1-C3) dialkylamino. In another embodiment, R9 is (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) alkoxy, (C1-C₃) haloalkoxy, (C1-C₃) hydroxyalkyl, -OH, or halogen. In yet another embodiment, R9 is (C1-C3) alkyl, (C1-C3) alkoxy, (C1-C₃) hydroxyalkyl, -OH, -NH2, (C1-C₃) alkylamino, or (C1-C3) dialkylamino. In another embodiment, R9 is -OH, -NH2, (C1-C3) alkylamino, or (C1-C₃) dialkylamino. In yet another embodiment, R9 is (C1-C3) hydroxyalkyl, -OH, -NH₂, (C1-C3) alkylamino, or (C1-C₃) dialkylamino. In another embodiment, R9 is -OH, -NH2, (C1-C₃) alkylamino, or (C1-C3) dialkylamino. In yet another embodiment, R9 is (C1-C3) hydroxyalkyl, -OH, or -NH2. In another embodiment, R9 is -OH or -NH₂. In yet another embodiment, R9 is -NH2.

[0096] In some embodiments of the Formulae above, R1o is H, (C1-C3) alkyl, (C₃-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the (C₃-C6) cycloalkyl,

heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH. In another embodiment, R1o is (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C6) cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In yet another embodiment, R1o is (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In another embodiment, R1o is (C3-C6) cycloalkyl optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH. In yet another embodiment, R1o is heterocycloalkyl optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In another embodiment, R1o is aryl optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -Nik, and -OH. In yet another embodiment, R1o is heteroaryl optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH.

[0097] In another embodiment, R1o is (C3-C6) cycloalkyl. In yet another embodiment, R1o is heterocycloalkyl. In another embodiment, R1o is heterocycloalkyl. In yet another embodiment,

R1o is aryl. In another embodiment, R1o is heteroaryl. In yet another embodiment, R1o is (C3-C6) cycloalkyl substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In another embodiment, R1o is heterocycloalkyl substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In yet another embodiment, R1o is aryl substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In another embodiment, R1o is heteroaryl substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH. In yet another embodiment, R1o is H or (C1-C3) alkyl. In another embodiment,

R1o is (C1-C3) alkyl. In yet another embodiment, R1o is H.

[0098] In some embodiments of the Formulae above, R11 is H, (C1-C3) alkyl, (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C6) cycloalkyl,

heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH. In another embodiment, R11 is (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C6) cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In yet another embodiment, R11 is (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In another embodiment, R11 is (C3-C6) cycloalkyl optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH. In yet another embodiment, R11 is heterocycloalkyl optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In another embodiment, R11 is aryl optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -Nik, and -OH. In yet another embodiment, R11 is heteroaryl optionally substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH.

[0099] In another embodiment, R11 is (C3-C6) cycloalkyl. In yet another embodiment, R11 is heterocycloalkyl. In another embodiment, R11 is heterocycloalkyl. In yet another embodiment,

R11 is aryl. In another embodiment, R11 is heteroaryl. In yet another embodiment, R11 is (C3-C6) cycloalkyl substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In another embodiment, R11 is heterocycloalkyl substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In yet another embodiment, R11 is aryl substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH₂, and -OH. In another embodiment, R11 is heteroaryl substituted with one or more substituents selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH. In yet another embodiment, R11 is H or (C1-C3) alkyl. In another embodiment,

R11 is (C1-C3) alkyl. In yet another embodiment, R11 is H.

[0100] In some embodiments of the Formulae above, R₁₀ and R11 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring optionally substituted with one to three substituents independently selected from (CI-CA) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, -OH, halogen, -Nft, (C1-C4) alkylamino, and (C1-C4) dialkylamino.

[0101] In some embodiments of the Formulae above, R₁₂ is H, (C1-C3) alkyl, or (C3-C6) cycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from CN, -NH2, -OH, and halogen. In another embodiment, R₁₂ is H or (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -NH₂, -OH, and halogen. In yet another embodiment, R12 is H or (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -OH, and halogen. In another embodiment, R₁₂ is H or (C1-C4) alkyl substituted with one or more substituents selected from CN, -NH2, -OH, and halogen. In yet another embodiment, R12 is H or (C1-C4) alkyl. In another embodiment, R₁₂ is (C3-C7) cycloalkyl or (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -NH2, -OH, and halogen. In yet another embodiment, R₁₂ is (C3-C7) cycloalkyl or (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -OH, and halogen. In another embodiment, R₁₂ is (C3-C7) cycloalkyl or (C1-C4) alkyl substituted with one or more substituents selected from CN, -NH₂, -OH, and halogen. In yet another embodiment, R₁₂ is (C3-C7) cycloalkyl or (C1-C4) alkyl substituted with one or more substituents selected from CN, -OH, and halogen. In another embodiment, R₁₂ is (C3-C7) cycloalkyl or (C1-C4) alkyl. In yet another embodiment, R₁₂ is H, (C1-C3) alkyl, or (C3-C6) cycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from CN, -OH, and halogen. In another embodiment, R12 is H.

[0102] In some embodiments of the Formulae above, R13 is H, (C1-C3) alkyl, or (C3-C6) cycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from CN, -NH2, -OH, and halogen. In another embodiment, R13 is H or (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -NH2, -OH, and halogen. In yet another embodiment, R13 is H or (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -OH, and halogen. In another embodiment, R13 is H or (C1-C4) alkyl substituted with one or more substituents selected from CN, -NH2, -OH, and halogen. In yet another embodiment, R13 is H or (C1-C4) alkyl. In another embodiment, R13 is (C3-C7) cycloalkyl or (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -NH2, -OH, and halogen. In yet another embodiment, R13 is (C3-C7) cycloalkyl or (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -OH, and halogen. In another embodiment, R₁₃ is (C3-C7) cycloalkyl or (C1-C4) alkyl substituted with one or more substituents selected from CN, -NH₂, -OH, and halogen. In yet another embodiment, R₁₃ is (C3-C7) cycloalkyl or (C1-C4) alkyl. In another embodiment, R₁₃ is H, (C1-C₃) alkyl, or (C₃-C6) cycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from CN, -OH, and halogen. In yet another embodiment, R₁₃ is H. In another embodiment, R₁₃ is (C1-C4) alkyl optionally substituted with one or more substituents selected from CN, -NH2, -OH, and halogen. In yet another embodiment, R1₃ is (C₃-C6) cycloalkyl. In another

embodiment, R13 is (C3-C7) cycloalkyl or (C1-C4) alkyl substituted with one or more substituents selected from CN, -OH, and halogen.

[0103] In some embodiments of the Formulae above, q is 1. In another embodiment, q is 2.

[0104] In some embodiments of the Formulae above, m is 0. In another embodiment, m is 1. In yet another embodiment, m is 2. In another embodiment, m is 3. In yet another embodiment, m is 0 or 1. In another embodiment, m is 1 or 2. In yet another embodiment, m is 2 or 3. In another embodiment, m is 0, 1, or 2. In yet another embodiment, m is 1, 2, or 3.

[0105] In some embodiments of the Formulae above, n is 0. In another embodiment, n is 1. In yet another embodiment, n is 2. In another embodiment, n is 3. In yet another embodiment, n is 0 or 1. In another embodiment, n is 1 or 2. In yet another embodiment, n is 2 or 3. In another embodiment, n is 0, 1, or 2. In yet another embodiment, n is 1, 2, or 3.

[0106] In some embodiments of the Formulae above, o is 0. In another embodiment, o is 1. In yet another embodiment, o is 2. In another embodiment, o is 3. In yet another embodiment, o is 0 or 1. In another embodiment, o is 1 or 2. In yet another embodiment, o is 2 or 3. In another embodiment, o is 0, 1, or 2. In yet another embodiment, o is 1, 2, or 3.

[0107] In some embodiments of the Formulae above, p is 0. In another embodiment, p is 1. In yet another embodiment, p is 2. In another embodiment, p is 3. In yet another embodiment, p is 0 or 1. In another embodiment, p is 1 or 2. In yet another embodiment, p is 2 or 3. In another embodiment, p is 0, 1, or 2. In yet another embodiment, p is 1, 2, or 3.

[0108] In some embodiments of the Formulae above, R₂ is H. In another embodiment, R2 is halogen. [0109] In some embodiments of the Formulae above, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6.

[0110] In some embodiments of the Formulae above, R1 is (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6 and R2 is H or halogen. In another embodiment, R\ is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6 and R2 is H or halogen. In another embodiment, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6 and R₂ is H. In another embodiment, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6 and R2 is halogen.

[0111] In some embodiments of the Formulae above, R1 and R3 when on adjacentatoms together with the carbon atoms to which they are attached form an aryl ring and R2 is H. In another embodiment, R1 and R3 when on adjacentatoms together with the carbon atoms to which they are attached form a heteroaryl ring and R2 is H.

[0112] In some embodiments of the Formulae above, R1 and R3 when on adjacentatoms together with the carbon atoms to which they are attached form an aryl ring.

[0113] In some embodiments of the Formulae above, R₄ is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0114] In some embodiments of the Formulae above, two R8 when on adjacent atoms form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9.

[0115] In some embodiments of the Formulae above, two R8 when on adjacent atoms form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9.

[0116] In another embodiment, two R8 when on the same carbon atom form a

spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0117] In some embodiments of the Formulae above, R9 is -NH_. [0118] In some embodiments of the Formulae above, R8 is halogen, -OH, -NR1oR11,

-C(0)NH₂, oxide, or (C1-C4) alkyl optionally substituted with one or more substituents selected from -NR₁₂R13 and OH.

[0119] In some embodiments of the Formulae above, R2 is H or halogen. In another embodiment, R₂ is H or halogen and R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R₄ is azetadinyl. In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, and n is 0.

[0120] In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR₁₀R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R₁₃ and -OH, and p is 0, l, or 2.

[0121] In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and two Rg on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9.

[0122] In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and two Rg on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and two Rg on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9. [0123] In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R₄ is pyrrolidinyl. In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, and n is 0. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R₄ is pyrrolidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH. In another embodiment, R2 is H or halogen,

R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R₄ is pyrrolidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R1₃ and -OH, and p is 0, 1, or 2.

[0124] In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more Rs, R1 is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more Rs.

[0125] In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R4 is piperidinyl. In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, and n is 0. In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R₄ is piperidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1, or 2.

[0126] In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0127] In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R₄ is piperazinyl. In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more Rs, R4 is piperazinyl, and n is 0. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R4 is piperazinyl. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR11,

-C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH, and p is 0, 1, or 2. [0128] In another embodiment, R₂ is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0129] In some embodiments of the Formulae above, R2 is H. In another embodiment, R₂ is H and R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6. In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R4 is azetadinyl. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, and n is 0. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R4 is azetadinyl. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1, or 2.

[0130] In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more Rs, R4 is azetadinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R₄ is azetadinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0131] In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R₄ is pyrrolidinyl. In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, and n is 0. In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R1₃ and -OH. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R₁₃ and -OH, and p is 0, 1, or 2.

[0132] In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more Rs. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the

heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0133] In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R₆, and R4 is piperidinyl. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, and n is 0. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R2 is H, R4 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH, and p is 0, 1, or 2.

[0134] In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the

heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0135] In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R4 is piperazinyl. In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, and n is 0. In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH, and p is 0, 1, or 2.

[0136] In another embodiment, R₂ is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R₄ is piperazinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the

heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R] is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and two Rx on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0137] In some embodiments of the Formulae above, R2 is halogen. In another embodiment, R2 is halogen and R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6. In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R₆, and R₄ is azetadinyl. In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, and n is 0. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NH_, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NHi, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R₁₃ and -OH, and p is 0, 1, or 2.

[0138] In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R.4 is azetadinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the

heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is azetadinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0139] In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R4 is pyrrolidinyl. In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, and n is 0. In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R1₃ and -OH. In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11,

-C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R1₃ and -OH, and p is 0, 1, or 2.

[0140] In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a (C₃-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R₆, R4 is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the

heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is pyrrolidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9. [0141] In another embodiment, R₂ is halogen, Ri is (C1-C4) haloalkyl, halogen, -OR5, or heteroaiyl optionally substituted with one or more R6, and R₄ is piperidinyl. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, and n is 0. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R₄ is piperidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R₄ is piperidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH, and p is 0, 1, or 2.

[0142] In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more Rs. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the

heterocycloalkyl ring is optionally substituted with one or more Rs. In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R₆, R4 is piperidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0143] In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, and R4 is piperazinyl. In another embodiment, R₂ is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, and n is 0. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1aR1i, -C(0)NH₂, or oxide, wherein the (C1-Gi) alkyl is optionally substituted with one or more substituents selected from -NR12R₁₃ and -OH. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR11,

-C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1, or 2.

[0144] In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the

heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is halogen, R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6, R4 is piperazinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0145] In some embodiments of the Formulae above, R₂ is H or halogen and R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R4 is azetadinyl. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is azetadinyl, and n is 0. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is azetadinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR11, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is azetadinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR11, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH, and p is 0, 1, or 2. [0146] In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen,

R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0147] In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is pyrrolidinyl. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, and n is 0. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NHi, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R₁₃ and -OH, and p is 0, 1, or 2.

[0148] In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0149] In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperidinyl. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, and n is 0. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR11, -C(0)NH_, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1, or 2.

[0150] In another embodiment, R₂ is H or halogen, R1 and Rs when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R1 is piperidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H or halogen, R1 and Rs when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0151] In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperazinyl, and n is 0. In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R4 is piperazinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperazinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1, or 2.

[0152] In another embodiment, R2 is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperazinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperazinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more Rs. In another embodiment, R₂ is H or halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperazinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0153] In some embodiments of the Formulae above, R₂ is H and R1 and Rs when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is azetadinyl. In another embodiment, R2 is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, and n is 0. In another embodiment, R2 is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH. In another embodiment, R2 is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is azetadinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH, and p is 0, 1, or 2.

[0154] In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R4 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0155] In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is pyrrolidinyl. In another embodiment, R₂ is H, R1 and Rs when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is pyrrolidinyl, and n is 0. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NHi, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH2, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1, or 2. [0156] In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R1 and R? when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0157] In another embodiment, R2 is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperidinyl. In another embodiment, R₂ is H, R1 and Rs when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, and n is 0. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NH_, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1 , or 2.

[0158] In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more Rs. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H, R1 and Rs when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0159] In another embodiment, R2 is H, R.\ and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperazinyl. In another embodiment, R2 is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, and n is 0. In another embodiment, R2 is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR1i, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR₁₀R1i, -C(0)NH_, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH, and p is 0, 1 , or 2.

[0160] In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is H, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0161] In some embodiments of the Formulae above, R₂ is halogen and R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is azetadinyl. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, and n is 0. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NRioR1i, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1, or 2.

[0162] In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is halogen, R1 and Rs when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is azetadinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is azetadinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0163] In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R4 is pyrrolidinyl. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is pyrrolidinyl, and n is 0. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is pyrrolidinyl, n is 0, and each R8 is

independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R13 and -OH. In another embodiment, R2 is halogen, R\ and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R4 is pyrrolidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR₁₂R₁₃ and -OH, and p is 0, 1, or 2.

[0164] In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is pyrrolidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0165] In another embodiment, R₂ is halogen, R1 and R₃ when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperidinyl. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, and n is 0. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and each R8 is

independently (C1-C4) alkyl, halogen, -OH, -NR1oR11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH. In another embodiment, R₂ is halogen, R1 and R₃ when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR1oR11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1 , or 2.

[0166] In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and two R8 on adjacent atoms together form a (C₃-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R.9. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperidinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0167] In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, and R₄ is piperazinyl. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, and n is 0. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, and each Rg is

independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R1₃ and -OH. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, each R8 is independently (C1-C4) alkyl, halogen, -OH, -NR10R11, -C(0)NH₂, or oxide, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13 and -OH, and p is 0, 1 , or 2.

[0168] In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, and two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more Rs. In another embodiment, R₂ is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, and two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9. In another embodiment, R2 is halogen, R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring, R₄ is piperazinyl, n is 0, and two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more Rs.

[0169] Non-limiting illustrative compounds of the disclosure include:

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine (1-1);

7-(4-amino-l-piperidyl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (1-2);

7-(2,8-diazaspiro[4.5]decan-8-yl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (1-3); 7-[4-(aminomethyl)- 1 -piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (1-4); 7-[3-(aminomethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (I-

5);

[l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3-yl]methanol (1-6); l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidine-3-carboxamide (1-7); l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3-(aminomethyl)pyrrolidin-3-ol

(i-8);

7-[3-(aminomethyl)-3-fluoro-pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2- amine (1-9);

7-[3-(l-aminoemyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (diastereomer A) (I- 10);

7-[3-(l-aminoemyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (diastereomer B) (1-11);

6- (2,6-dichlorophenyl)-7-[4-(methylaminomethyl)-l-piperidyl]pyrido[2,3-d]pyrimidin-2-amine (1-12);

7- [3-(l-aminoethyl)azetidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (1-13);

7-[4-(l -aminoethyl)- 1 -piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (1-14);

7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-b]pyrrol-5-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine (1-15); 3 - [ [ 1 - [2-amino-6-(2,6-dichlorophenyl)py rido[2, 3-d] pyrimidin-7-yl]pyrrolidin-3 - yl]methylamino]propanenitrile (I- 16);

2-(((l-(2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3- yl)methyl)amino)ethan-l-ol (1-17);

7-[3-[(cyclopropylamino)methyl]pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidi 2-amine (1-18);

6- (2,6-dichlorophenyl)-7-[3-[(2,2-difluoroethylamino)methyl]pyrrolidin-l-yl]pyrido[2,3- d]pyrimidin-2-amine (1-19);

[3-amino-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yljmethanol (1-20);

[(3R,4R)-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-4- (hy droxymethy l)pyrrolidin-3 -yl] methanol (1-21) ;

7- (3 -aminopyrrolidin- 1 -yl)-6-( 1 -naphthyl)pyrido[2,3-d]pyrimidin-2-amine (1-22);

7-(3-aminoazetidin-l-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine (1-23);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(l-mphthyl)pyrido[2,3-d]pyrimidin-2- amine (1-24);

7-(2,8-diazaspiro[4.5]decan-8-yl)-6-(l -naphthyl)pyrido[2,3-d]pyrimidin-2-amine (1-25);

7-(2,7-diazaspiro[3.5]nonan-7-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine (1-26);

7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-c]pyrrol-5-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidm 2-amine (1-27);

7-[3-(aminomethyl)azetidin-l -yl]-6-(l -naphthyl)pyrido[2,3-d]pyrimidin-2-amine (1-28);

6- (l -naphthyl)-7-piperazin-l -yl-pyrido[2,3-d]pyrimidin- 2-amine (1-29);

7- (3-aminoazetidin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-30);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(5-fluoro-6-methoxy-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-31);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methyl-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-32); 2- [4- [2- [2-amino-7- [( 1 R, 5 S,6s)-6-amino-3 -azabicycto

6- yl]-3-chloro-phenyl]pyrazol-l-yl]acetic acid (1-33);

7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methoxy-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-34);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methylthiazol-5- yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-35);

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-ethoxy-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-36);

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-[6-(dimethylamino)-3- pyridyl]phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-37);

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(4-pyridyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine (1-38);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-methyl-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-39);

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(l-methylpyrazol-4- yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-40);

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-methoxy-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-41);

N-[5-[2-[2-amino-7-[(lR,5S, 6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d] pyrimidin-6-yl]-3-chloro-phenyl]-2-pyridyl]methanesulfonamide (1-42);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-43);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-isobutoxy- phenyl)pyrido[2,3-d]pyrimidin-2-amine (1-44);

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6- (cyclopropylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-45); 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-46);

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-methoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine (1-47);

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-bromo-6-methoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine (1-48);

7-[(lR,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine (1-49);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(te1rahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-50);

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(te1rahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-51);

2- [2- [2-amino-7- [( 1 R, 5 S)-6-amino-3 -azabicycto

3- chloro-phenoxy]acetic acid (1-52);

4- [2- [2-amino-7- [( 1 R, 5 S)-6-amino-3 -azabicyd^

3-chloro-phenoxy]butanoic acid (1-53);

7- [(3R)-3 -(aminomethy l)pyrrolidin- 1 -yl] -6-(2-chloro-6-isobutoxy-phenyl)pyrido[2, 3 - d]pyrimidin-2-amine (1-54);

7- [(3 S)-3 -(aminomethyl)pyrrolidin- 1 -yl] -6-(2-chloro-6-isobutoxy-phenyl)pyrido [2,3 - d]pyrimidin-2-amine (1-55);

7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine (1-56);

7-(4-methylpiperazin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-57);

6-(2-ethoxyphenyl)-7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)pyrido[2,3-d]pyrimidin-2-amine (1-58);

6-(2-ethoxyphenyl)-7-(4-methylpiperazin-l-yl)pyrido[2,3-d]pyrimidin-2-amine (1-59); and 6-(2-chloro-6-isobutoxy-phenyl)-7-[3-(5-fluoro-2-methyl-anilino)pyrrolidin-l-yl]pyrido[2,3- d]pyrimidin-2-amine (1-60).

[0170] In some embodiments, disclosed herein are pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers of any one of compounds 1-1 to 1-60 described above.

[0171] In certain embodiments, the compound of Formula (I) is:

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomers thereof.

[0172] In another embodiment of the disclosure, the compounds of Formula (I) are enantiomers. In some embodiments the compounds are the (S)-enantiomer. In other embodiments the compounds are the (i?)-enantiomer. In yet other embodiments, the compounds of Formula (I) may be (+) or (-) enantiomers. [0173] It should be understood that all isomeric forms are included within the present disclosure, including mixtures thereof. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans configuration. All tautomeric forms are also intended to be included.

[0174] Compounds of the disclosure, and pharmaceutically acceptable salts, hydrates, solvates, stereoisomers and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present disclosure.

[0175] The compounds of the disclosure may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the disclosure as well as mixtures thereof, including racemic mixtures, form part of the present disclosure. In addition, the present disclosure embraces all geometric and positional isomers. For example, if a compound of the disclosure incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Each compound herein disclosed includes all the enantiomers that conform to the general structure of the compound. The compounds may be in a racemic or enantiomerically pure form, or any other form in terms of stereochemistry. The assay results may reflect the data collected for the racemic form, the enantiomerically pure form, or any other form in terms of stereochemistry.

[0176] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of the disclosure may be atropisomers (e.g., substituted biaryls) and are considered as part of this disclosure. Enantiomers can also be separated by use of a chiral HPLC column. [0177] It is also possible that the compounds of the disclosure may exist in different tautomeric forms, and all such forms are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.

[0178] All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this disclosure, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I)incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the disclosure. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the disclosure.) Individual stereoisomers of the compounds of the disclosure may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present disclosure can have the S or R configuration as defined by the IUPAC 1974 R6commendations. The use of the terms "salt", "solvate", "ester," "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.

[0179] The compounds of Formula I may form salts which are also within the scope of this disclosure. R6ference to a compound of the Formula herein is understood to include reference to salts thereof, unless otherwise indicated.

[0180] The present disclosure relates to compounds which are modulators of AccC. In one embodiment, the compounds of the present disclosure are inhibitors of AccC.

[0181] The disclosure is directed to compounds as described herein and pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein, or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

[0182] The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0183] The compounds of Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I).

[0184] Those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (I). Accordingly, the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and/or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. R6solution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley- lnterscience, 1994).

[0185] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. Preparation of compounds

[0186] The compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Compounds of the present disclosure can be synthesized by following the steps outlined in General Scheme 1 which comprises an example of sequence of assembling intermediates la-lh. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated. Preferred methods include but are not limited to those methods described below.

General Scheme 1

wherein R1, R_, R3, R4, R8, n and p are as defined herein above for Formula (I).

[0187] The general manner of preparing target compounds of Formula (I) by using intermediates la-lh is outlined above in General Scheme 1. Cyclization of la with lb in the presence of a base (e.g., sodium hydride (NaH)) and in a solvent (e.g., dimethylformamide (DMF)) provides intermediate lc. Treatment of lc with sodium nitrite and an acid (e.g., trifluoroacetic acid (TFA)) optionally in a solvent provides Id. Chlorination of Id using POCI3 in a solvent (e.g., DMF) and optionally at elevated temperature provides le. Nucleophilic addition of If to le in the presence of a base (e.g., N,iV"-diisopropylethylamine) and in a solvent (e.g., acetonitrile (ACN) and/or dioxane) provides intermediate lg. Oxidation of lg with an oxidizing agent (e.g., 3-chloroperbenzoic acid) in a solvent (e.g., dichloromethane (DCM)) provides intermediate lh. Treatment of lh ammonia in a solvent (e.g., tetrahydrofuran (THF) and/or methanol (MeOH)) at elevated temperature provides the desired product of Formula (I). It should be understood that the General Scheme 1 may include one or more additional steps. For example, in certain embodiments, at least one R8 in If, lg, and/or lh is -NHBoc, and General Scheme 1 includes a Boc-deprotection step to produce (I) wherein at least one R8 is -NH₂.

[0188] Compounds of Formula (Γ) can exist as enantiomeric or diastereomeric stereoisomers. Enantiomerically pure compounds of Formula (Γ) can be prepared using enantiomerically pure chiral building blocks. Alternatively, racemic mixtures of the final compounds or a racemic mixture of an advanced intermediate can be subjected to chiral purification as described herein below to deliver the desired enantiomerically pure intermediates or final compounds. In the instances where an advanced intermediate is purified into its individual enantiomers, each individual enantiomer can be carried on separately to deliver the final enantiomerically pure compounds of Formula (I).

Methods of Using the Disclosed Compounds

[0189] Another aspect of the disclosure relates to a method of treating a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0190] Another aspect of the disclosure relates to a method of preventing a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of an AccC-inhibitory compound disclosed herein, or a

pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0191] Another aspect of the disclosure relates to a method of reducing the risk of a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0192] Another aspect of the present disclosure relates to a method of treating a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a pharmaceutical composition comprising an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0193] Another aspect of the present disclosure relates to a method of preventing a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a pharmaceutical composition comprising an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0194] Another aspect of the present disclosure relates to a method of reducing the risk of a bacterial infection. The method comprises administering to a patient in need of a treatment for a bacterial infection an effective amount of a pharmaceutical composition comprising an AccC- inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0195] The present disclosure also relates to the use of an inhibitor of AccC for the preparation of a medicament used in the treatment of a bacterial infection, wherein the medicament comprises an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0196] The present disclosure also relates to the use of an inhibitor of AccC for the preparation of a medicament used in the prevention of a bacterial infection, wherein the medicament comprises an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0197] The present disclosure also relates to the use of an inhibitor of AccC for the preparation of a medicament used in the reduction of the risk of a bacterial infection, wherein the medicament comprises an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. [0198] Another aspect of the present disclosure relates to the use of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the treatment of a bacterial infection.

[0199] Another aspect of the present disclosure relates to the use of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the prevention of a bacterial infection.

[0200] Another aspect of the present disclosure relates to the use of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the reduction of the risk of a bacterial infection.

[0201] In another aspect, the present disclosure relates to the use of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for treating a bacterial infection.

[0202] In another aspect, the present disclosure relates to the use of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for preventing a bacterial infection.

[0203] In another aspect, the present disclosure relates to the use of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, in the manufacture of a medicament for reducing the risk of a bacterial infection.

[0204] Another aspect of the present disclosure relates to a method of inhibiting a carboxylase enzyme in gram-negative bacteria, thereby affecting bacterial growth, comprising administering to a patient in need of such inhibition an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0205] Another aspect of the present disclosure relates to a method of inhibiting a carboxylase enzyme in gram-positive bacteria, thereby affecting bacterial growth, comprising administering to a patient in need of such inhibition an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0206] Another aspect of the present disclosure relates to a method of inhibiting AccC, thereby modulating the virulence of a bacterial infection, comprising administering to a patient in need of such inhibition an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0207] Another aspect of the present disclosure relates to a method for treating a patient having a bacterial infection comprising administering to the patient in need thereof an antibacterially effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In a more specific embodiment of the method of treatment, the bacterial infection is a gram- negative bacterial infection. In a further specific embodiment the patient is a mammal and in certain embodiments, a human.

[0208] Another aspect of the present disclosure relates to a method for treating a patient having a bacterial infection comprising administering to the patient in need thereof an antibacterially effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. In a more specific embodiment of the method of treatment, the bacterial infection is a gram-positive bacterial infection. In a further specific embodiment the patient is a mammal and in certain embodiments, a human.

[0209] Another aspect of the present disclosure relates to a method of administering an antibacterially effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with a fermentative or non-fermentative gram-negative bacteria. Examples of such bacteria include, but are not limited to, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Haemophilus, Franciscellaceae (e.g., Franciscella tularensis), Neisseria species, Enter obacleriaceae, such as Serralia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Yersinia (e.g., Yersinia pestis), Morganella, Cedecea, Edwardsiella species and Escherichia coli. In some embodiments, the gram negative bacteria is Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, A!caligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Franciscellaceae or a Neisseria species.

[0210] Another aspect of the present disclosure relates to a method of administering an antibacterially effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with gram-negative bacteria. Examples of such bacteria include, but are not limited to, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Haemophilus, Franciscellaceae (e.g., Franciscella tularensis), Neisseria species, Enterobacteriaceae, such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Yersinia (e.g., Yersinia pestis), Morganella, Cedecea, Edwardsiella species and Escherichia coli. In some embodiments, the gram negative bacteria is Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Franciscellaceae or a Neisseria species.

[0211] Another aspect of the present disclosure relates to a method of administering an antibacterially effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with gram-positive bacteria. Examples of such bacteria include

Staphylococcus, Streptococcus, Enterococcus, Bacillus, Clostridium and Listeria species.

[0212] The present disclosure further provides methods of treating, preventing, or reducing the risk of a bacterial infection associated with inhibition of AccC comprising administering to a subject an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0213] The present disclosure provides inhibitors of AccC that are therapeutic agents in the treatment of bacterial infections, including, but not limited to, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans,

Enterobacteriaceae, Haemophilus, Franciscellaceae (e.g., Franciscella tularensis), Neisseria species, Enterobacteriaceae, such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Yersinia (e.g., Yersinia pestis), Morganella, Cedecea, Edwardsiella species, Acinetobacter, Mycobacterium, and Escherichia coli. Ultimately, the present disclosure provides the medical community with novel compounds and pharmacological strategy for the treatment of bacterial infections associated with AccC enzymes.

[0214] In another aspect, the present disclosure provides a method of inhibiting AccC, thereby modulating the virulence of a bacterial infection, comprising administering to a patient in need of such inhibition an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof In certain embodiments of the method of inhibiting AccC using a compound of the present disclosure, the IC50 value of the compound is less than or equal to 10 μΜ with respect to AccC. In other embodiments, the IC50 value is less than or equal to 1 μΜ, is less than or equal to 0.1 μΜ, is less than or equal to 0.050 μΜ, is less than or equal to 0.030 μΜ, is less than or equal to 0.025 μΜ, or is less than or equal to 0.010 μΜ.

[0215] In another aspect, the present disclosure provides a method for treating a patient having a gram-negative bacterial infection comprising administering to the patient in need thereof an antibacterially effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0216] In another aspect, the present disclosure provides a method for treating a patient having a gram-positive bacterial infection comprising administering to the patient in need thereof an antibacterially effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0217] In another aspect, the present disclosure provides a method of administering a therapeutically effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with a fermentative or non-fermentative gram-negative bacteria. Examples of fermentative or non-fermentative gram-negative bacteria include but are not limited to,

Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Franciscellaceae {e.g., Franciscella tularensis), Neisseria species, Enterobacteriaceae, such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Yersinia {e.g., Yersinia pestis), Morganella, Cedecea, Edwardsiella species, Acinetobacter, Mycobacterium, and Escherichia coli. In some embodiments, the gram negative bacteria is Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Franciscellaceae or a Neisseria species.

[0218] In another aspect, the present disclosure provides a method of administering an inhibitory amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with a gram-negative bacteria, such as Enterobacteriaceae which is selected from the group consisting of organisms such as Serratia, Proteus, Klebsiella, Enterobacter, Citrobacter, Salmonella, Providencia, Yersinia {e.g., Yersinia pestis), Morganella, Cedecea, Edwardsiella species and Escherichia coli.

[0219] In another aspect, the present disclosure provides a method of administering an inhibitory amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, to a patient infected with a gram-positive bacteria, such as Staphylococcus, Streptococcus, Enterococcus, Bacillus, Clostridium and Listeria species.

[0220] In certain embodiments, the patient may be a mammal, and in some embodiments, a human.

[0221] Bacterial infections susceptible to treatment according to the present disclosure include primary infections and co-infections caused by a species of bacteria and one or more additional infectious agents such as, for example, bacteria, virus, parasite and fungus.

[0222] Compounds of the disclosure can be used alone or in combination with a second antibacterial agent for the treatment of a serious or chronic respiratory tract infection including serious lung and nosocomial infections such as those caused by Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Alcaligenes xylosoxidans, Flavobacterium meningosepticum, Providencia stuartii and Citrobacter freundi, community lung infections such as those caused by

Haemophilus Influenzae, Legionella species, Acinetobacter, Mycobacterium, Moraxella catarrhalis, Branhamella catarrhalis, Enterobacter species, Klebsiella species, and Proteus species, infections caused by other bacterial species such as Neisseria species, Shigella species, Salmonella species, Helicobacter pylori, Vibrionaceae and Bordetella species, as well as infections caused by a Brucella species, Francisella tularensis and/or Yersinia Pestis.

[0223] The present disclosure provides novel combinations of compounds including an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, as well as methods for treating patients infected with gram-negative or gram-positive bacteria. The novel combinations provided herein can be formulated into pharmaceutical formulations and medicaments that are useful in the methods of the disclosure. The disclosure also provides for the use of the novel combinations in preparing medicaments and pharmaceutical formulations, for use of the combinations in treating bacterial infections in a patient.

[0224] In one embodiment, a second antibacterial agent is used in combination with an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. Examples of suitable second antibacterial agents include, but are not limited to, vancomycin, linezolid, azithromycin, imipenem, teicoplanin, daptomycin, clindamycin, rifampin, cefotaxime, gentamicin, novobiocin or telavancin. In one such embodiment, the antibacterial agent is vancomycin, teicoplanin, rifampin, azithromycin, telavancin or novobiocin. Most preferably, the antibacterial agent is vancomycin or rifampin. In some embodiments of the disclosure, the antibacterial agent and/or AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, is administered at a sub-therapeutic dose, wherein a subtherapeutic dose is a dose that would be insufficient to treat bacterial infections, if administered alone.

[0225] One therapeutic use of the compounds or compositions of the present disclosure which inhibit AccC is to provide treatment to patients or subjects suffering from a bacterial infection.

[0226] The disclosed compounds of the disclosure can be administered in effective amounts to treat or prevent a disorder and/or prevent the development thereof in subjects.

[0227] Another aspect of the disclosure is directed to pharmaceutical compositions or formulations comprising an effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0228] Administration of the disclosed compounds can be accomplished via any mode of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.

[0229] Depending on the intended mode of administration, the disclosed compositions can be in solid, semi-solid or liquid dosage form, such as, for example, injectables, tablets,

suppositories, pills, time-release capsules, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, or the like, sometimes in unit dosages and consistent with conventional

pharmaceutical practices. Likewise, they can also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular form, and all using forms well known to those skilled in the pharmaceutical arts.

[0230] The disclosed compounds can be also formulated as a suppository that can be prepared from fatty emulsions or suspensions; using polyalkylene glycols such as propylene glycol, as the carrier.

[0231] Pharmaceutical compositions of the present disclosure comprise a therapeutically effective amount of an AccC-inhibitory compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, formulated together with one or more pharmaceutically acceptable carriers or diluents. As used herein, the term "pharmaceutically acceptable carrier" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0232] The pharmaceutical compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally (as by intravenous, intramuscular or subcutaneous injection), intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray, or a liquid aerosol or dry powder formulation for inhalation.

[0233] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuifuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0234] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, 1% lidocaine, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0235] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0236] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally

administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and

poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

[0237] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0238] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and/or glycine; b) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, c) binders such as, for example, carboxymethylcellulose, alginates, magnesium aluminum silicate, starch paste, gelatin, sucrose, acacia, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) humectants such as glycerol, e) disintegrating agents such as starches, agar, cellulose and its derivatives such as sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose and cellulose acetate, calcium carbonate, sodium carbonate, potato or tapioca starch, certain silicates, bentonite, xanthan gum, algic acid or its sodium salt, or effervescent mixtures; f) solution retarding agents such as paraffin, g) absorption accelerators such as quaternary ammonium compounds, h) wetting agents such as, for example, acetyl alcohol and glycerol monostearate, i) absorbents such as kaolin and bentonite clay; j) lubricants such as silica, talcum, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, sodium lauryl sulfate, and mixtures thereof; k) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or 1) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl- cyclodextrin, PEG400, PEG200. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0239] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0240] The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the acti ve ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0241] The antibacterial compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.

Examples of embedding compositions that can be used include polymeric substances and waxes.

[0242] Dosage forms for topical or transdermal administration of a compound of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this disclosure.

[0243] The ointments, pastes, creams and gels may contain, in addition to an active compound of this disclosure, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof

[0244] Compositions of the disclosure may also be formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles where bacteria reside in patients with bronchial infections, such as chronic bronchitis and pneumonia.

Pathogenic bacteria are commonly present throughout airways down to bronchi, bronchioli and lung parenchema, particularly in terminal and respiratory bronchioles. During exacerbation of infection, bacteria can also be present in alveoli. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0245] Aerosolized formulations of the disclosure may be delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of an aerosol particles having with a mass medium average diameter

predominantly between 1 to 5 μm. Further, the formulation preferably has balanced osmolarity ionic strength and chloride concentration, and the smallest aerosolizable volume able to deliver effective dose of the compounds of the disclosure to the site of the infection. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.

[0246] Aerosolization devices suitable for administration of aerosol formulations of the disclosure include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation of the disclosure into aerosol particle size predominantly in the size range from 1-5 pm. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are 1 to 5 μιη range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb and AeroDose vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, Calif), Sidestream7 nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC7 and Pari LC Star7 jet nebulizers (Pari R6spiratory Equipment, Inc., Richmond, Va.), and Aerosonic (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and μΐΛ¾ΑίΓε7 (Omron Healthcare, Inc., Vernon Hills, 111.) ultrasonic nebulizers.

[0247] Compounds of the disclosure may also be formulated for use as topical powders and sprays that can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.

[0248] Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. [0249] According to the methods of treatment of the present disclosure, bacterial infections are treated or prevented in a patient such as a human or lower mammal by administering to the patient a therapeutically effective amount of a compound of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, in such amounts and for such time as is necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the disclosure is meant a sufficient amount of the compound to treat bacterial infections, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.

[0250] Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the disclosed compound by weight or volume.

[0251] Effective dosage amounts of the disclosed compounds, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the disclosed compound as needed to treat the condition. Compositions for in vivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosed compound, or, in a range of from one amount to another amount in the list of doses. In one embodiment, the compositions are in the form of a tablet that can be scored.

[0252] Methods of formulation are well known in the art and are disclosed, for example, in R6mington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 19th Edition (1995). Pharmaceutical compositions for use in the present disclosure can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art.

[0253] A "kit" as used in the instant application includes a container for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet. The container can be in any conventional shape or form as known in the art that is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a glass or plastic bottle or jar, a resealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. The container employed can depend on the exact dosage form involved, for example a conventional cardboard box would not generally be used to hold a liquid suspension. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle that is in turn contained within a box.

[0254] An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil that is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

[0255] Another specific embodiment of a kit is a dispenser designed to dispense the daily doses one at a time in the order of their intended use. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter, that indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal that, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

[0256] The kits of the present disclosure may also include, in addition to a compound of the present disclosure, one or more additional pharmaceutically active compounds. For example, the additional compound second antibacterial. The additional compounds may be administered in the same dosage form as the compound of the present disclosure or in a different dosage form. Likewise, the additional compounds can be administered at the same time as the compound of the present disclosure or at different times.

[0257] Compositions of the present compounds may also be used in combination with other known antibacterial agents of similar spectrum to (1) enhance treatment of severe gram-negative infections covered by the spectrum of this compound or (2) add coverage in severe infections in which multiple organisms are suspected in which another agent of a different spectrum may be required in addition to this compound. Potential agents include members of the

aminoglycosides, penicillins, cephalosporins, fluoroquinolones, macrolides, glycopeptides, lipopeptides and oxazolidinones. The treatment can involve administering a composition having both a compound of the present disclosure and a second antibacterial compound or

administration of a compound of the present inventive compounds followed by or preceded by administration of a second antibacterial agent.

[0258] The foregoing may be better understood by reference to the following examples, that are presented for illustration and not to limit the scope of the inventive concepts.

Exemplary Embodiments

[0259] Embodiment 1-1. A compound of Formula (I):

NH₂

(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:

R1 is (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R6;

R₂ is H, (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5', aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7;

R3 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -OH, -NH₂, (C1-C4) alkylamino, or (C1-C4) dialkylamino;

or R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring; or R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form a heteroaryl ring;

R4 is a heterocycloalkyl ring;

R5 is (C1-C6) alkyl, -(CH₂)m(C3-C7) cycloalkyl, or -(CH₂)_mheterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

R5¹ is (C1-C6) alkyl, -(CH₂)o(C3-C7) cycloalkyl, or -(CH₂)₀heterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R6 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, halogen, -NH₂, (C1-C4) alkylamino, (C1-C4) dialkylamino, or

-N(H)S(0)q (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R7 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, halogen, -NH₂, (C1-C4) alkylamino, (C1-C4) dialkylamino, or

-N(H)S(0)q (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R8 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, halogen, -OH, -CN, -NR10R11, -C(0)NH₂, or oxide, wherein the

(C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13, -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

or two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9; or two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9; or two R8 on the same carbon atom together form a (C3-C7) spirocycloalkyl ring, wherein the spirocycloalkyl ring is optionally substituted with one or more R9; or two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the

spiroheterocycloalkyl ring is optionally substituted with one or more R9;

each R9 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, -OH, halogen, -CN, -NH₂, (C1-C4) alkylamino, or (C1-C4) dialkylamino;

each R1o and R11 is independently H, (C1-C4) alkyl, (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C6) cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from (C1-C4) alkyl,

(C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C₄) haloalkoxy, halogen, CN, -NH2, and -OH; or

R₁₀ and R11 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, -OH, halogen, -NH₂, (C1-C4) alkylamino, and (C1-C4) dialkylamino;

each R₁₂ and Ru is independently H, (C1-C4) alkyl, or (C3-C7) cycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from CN, -NH2, -OH, and halogen;

q is 1 or 2; and

each m, n, o, and p is independently 0, 1, 2, or 3.

[0260] Embodiment 1-2. The compound of Embodiment 1-1 , wherein R₂ is H or halogen.

[0261] Embodiment 1-3. The compound of Embodiment 1-1 or 1-2, wherein R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6.

[0262] Embodiment 1-4. The compound of Embodiment 1-1 or 1-2, wherein R1 and R3 together with the carbon atoms to which they are attached form an aryl ring.

[0263] Embodiment 1-5. The compound of any one of Embodiments 1-1 to 1-4, wherein R₄ is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

[0264] Embodiment 1-6. The compound of any one of Embodiments 1-1 to 1-5, wherein two R8 when on adjacent atoms form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9.

[0265] Embodiment 1-7. The compound of any one of Embodiments I- 1 to 1-5, wherein two R8 when on adjacent atoms form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9.

[0266] Embodiment 1-8. The compound of any one of Embodiments 1-1 to 1-5, wherein two R8 when on the same carbon atom form a spiroheterocycloalkyl ring, wherein the

spiroheterocycloalkyl ring is optionally substituted with one or more R9.

[0267] Embodiment 1-9. The compound of any one of Embodiments 1-1 to 1-8, wherein R9 is -ΝΚ».

[0268] Embodiment 1-10. The compound of any one of Embodiments 1-1 to 1-5, wherein R8 is halogen, -OH, -NR4oR1i, -C(0)NH2, oxide, or (C1-C4) alkyl optionally substituted with one or more substituents selected from -NR12R13 and OH. [0269] Embodiment I- 11. The compound of Embodiment I- 1 , having Formula (la) :

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0270] Embodiment 1-12. The compound of Embodiment 1-1, having Formula (lb):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0271] Embodiment 1-13. The compound of Embodiment I- 1 , having Formula (Ic) :

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0272] Embodiment 1-14. The compound of Embodiment 1-1, having Formula (Id):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0273] Embodiment 1-15. The compound of Embodiment I- 1 , having Formula (le) or Formula (If):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0274] Embodiment 1-16. The compound of Embodiment 1-1, having Formula (Ig):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. [0275] Embodiment 1-17. The compound of Embodiment 1-1, having Formula (Ih):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0276] Embodiment 1-18. The compound of Embodiment 1-1, having Formula (Ii):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0277] Embodiment 1-19. The compound of Embodiment 1-1, having Formula (Ij):

(Ij),

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0278] Embodiment 1-20. The compound of Embodiment 1-1 selected from the group consisting of:

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-(4-amino-l-piperidyl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,8-diazaspiro[4.5]decan-8-yl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[4-(aminomethyl)-l-piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[3-(aminomethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

[l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3-yl]methanol;

l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidine-3-carboxamide; l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3-(aminomethyl)pyrrolidin-3-ol;

7- [3 -(aminomethy l)-3 -fluoro-pyrrolidin- 1 -y 1] -6-(2, 6-dichlorophenyl)pyrido[2, 3-d] pyrimidin-2- amine;

7-[3-(l-aminoethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine; 6-(2,6-dichlorophenyl)-7-[4-(methylaminomethyl)-l-piperidyl]pyrido[2,3-d]pyrimidin-2-amine; 7-[3-(l-aminoethyl)azetidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7- [4-( 1 -aminoethy 1)- 1 -piperidyl] -6-(2,6-dichlorophenyl)pyrido[2, 3-d] pyrimidin-2-amine;

7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-b]pyrrol-5-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine;

3 - [ [ 1 - [2-amino-6-(2,6-dichlorophenyl)py rido[2, 3-d] pyrimidin-7-yl]pyrrolidin-3 - yl]methylamino]propanenitrile;

2-(((l-(2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3- yl)methyl)amino)ethan- 1 -ol;

7-[3-[(cyclopropylamino)methyl]pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidi 2-amine;

6- (2,6-dichlorophenyl)-7-[3-[(2,2-difluoroethylamino)methyl]pyrrolidin-l-yl]pyrido[2,3- d]pyrimidin-2-amine;

[3-amino-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yl]methanol;

[(3R,4R)-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-4- (hydroxymethyl)pyrrolidin-3-yl]methanol;

7- (3 -aminopyrrolidin- 1 -yl)-6-( 1 -naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(3-aminoazetidin-l-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3J^]hexan-3-yl)-6-(l-mphthyl)pyrido[2,3-d]pyrimidm-2- amine;

7-(2,8-diazaspiro[4J]decan-8-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,7-diazaspiro[3.5]nomn-7-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-c]pyrrol-5-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidm 2-amine;

7-[3-(aminomethyl)azetidin-l -yl]-6-(l -naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

6-(l-naphthyl)-7-piperazin-l-yl-pyrido[2,3-d]pyrimidin- 2-amine; 7-(3-aminoazetidin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-ami

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(5-fluoro-6-methoxy-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methyl-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

2-[4-[2-[2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyrido[2,3-d]pyrimidin-

6- yl]-3-chloro-phenyl]pyrazol- 1 -yl]acetic acid;

7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methoxy-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methylthiazol-5- yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-(6-ethoxy-3 - pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6- [6-(dimethy lamino)-3 - pyridyl]phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(4-pyridyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-methyl-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-( 1 -methylpyrazol-4- yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-(6-methoxy-3 - pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

N-[5-[2-[2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-

6- yl]-3-chloro-phenyl]-2-pyridyl]methanesulfonamide;

7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine; 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-isobutoxy- phenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6- (cyclopropylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-methoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-bromo-6-methoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(te1rahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3J.0]hexan-3-yl]-6-[2-chloro-6-(te1rahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

2- [2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-6-yl^

3- chloro-phenoxy]acetic acid;

4- [2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-6-yl^ 3-chloro-phenoxy]butanoic acid;

7- [(3R)-3 -(aminomethy l)pyrrolidin- 1 -yl] -6-(2-chloro-6-isobutoxy-phenyl)pyrido[2, 3 - d]pyrimidin-2-amine;

7- [(3 S)-3 -(aminomethyl)pyrrolidin- 1 -yl] -6-(2-chloro-6-isobutoxy-phenyl)pyrido [2,3 - d]pyrimidin-2-amine;

7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine;

7-(4-methylpiperazin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine; 6-(2-et oxyphenyl)-7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)pyrido[2,3-d]pyrimidin-2-

6-(2-ethoxypheny l)-7-(4-methy lpiperazin- 1 -yl)pyrido[2,3 -d]pyrimidin-2-amine; and

6-(2-chloro-6-isobutoxy-phenyl)-7-[3-(5-fluoro-2-methyl-anilino)pyrrolidin-l-yl]pyrido[2,3- d]pyrimidin-2-amine.

[0279] Embodiment 1-21. A pharmaceutical composition comprising a compound of any one of Embodiments 1-1 to 1-20 and a pharmaceutically acceptable carrier.

[0280] Embodiment 1-22. A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments 1-1 to 1-20.

[0281] Embodiment 1-23. The method according to Embodiment 1-22, wherein said bacterial infection is a gram-negative bacterial infection.

[0282] Embodiment 1-24. The method according to Embodiment 1-23, wherein said gram- negative bacterial infection is Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enter obacteriaceae, Haemophilus,

Franciscellaceae or a Neisseria species.

[0283] Embodiment 1-25. The method according to Embodiment 1-22, wherein said bacterial infection is a gram-positive bacterial infection.

[0284] Embodiment 1-26. The method according to Embodiment 1-25, wherein said gram- positive is Staphylococcus, Streptococcus, Enterococcus, Mycobacterium, Bacillus, Clostridium or a Listeria species.

[0285] Embodiment 1-27. A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to Embodiment 1-21.

[0286] Embodiment 1-28. The method according to Embodiment 1-27, wherein said bacterial infection is a gram-negative bacterial infection.

[0287] Embodiment 1-29. The method according to Embodiment 1-28, wherein said gram- negative bacterial infection is Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enter obacteriaceae, Haemophilus, Acinetobacter, Franciscellaceae or a Neisseria species.

[0288] Embodiment 1-30. The method according to Embodiment 1-27, wherein said bacterial infection is a gram-positive bacterial infection.

[0289] Embodiment 1-31. The method according to Embodiment 1-30, wherein said gram- positive bacterial infection is Staphylococcus, Streptococcus, Enterococcus, Bacillus,

Clostridium, or a Listeria species.

[0290] Embodiment Π-l. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:

R1 is (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R6;

R₂ is H, (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5', aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7;

R3 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -OH, -NH₂, (C1-C4) alkylamino, or (C1-C4) dialkylamino;

or R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring; or R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form a heteroaryl ring; R4 is a heterocycloalkyl ring;

R5 is (d-d) alkyl, -(CH₂)m(C3-C7) cycloalkyl, or -(CH₂)mheterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

R5' is (C1-C6) alkyl, -(CH_)o(C3-C7) cycloalkyl, or -(CH₂)₀heterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from the group consisting of -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R6 is independently (d-d) alkyl, (d-d) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, halogen, -NH₂, (C1-C4) alkylamino, (C1-C4) dialkylamino, or

-N(H)S(0)_q (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from the group consisting of -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl; each R7 is independently (d-d) alkyl, (d-d) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, halogen, -NH₂, (C1-d) alkylamino, (C1-C4) dialkylamino, or

-N(H)S(0)_q (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from the group consisting of -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl; each R8 is independently (d-d) alkyl, (d-d) haloalkyl, (C1-d) alkoxy,

(C1-C4) haloalkoxy, halogen, -OH, -CN, -NR10R11, -C(0)NH₂, or oxide, wherein the

(d-d) alkyl is optionally substituted with one or more substituents selected from the group consisting of -NR₁₂R13, -C(0)OH, -OH, and -C(0)0(d-d) alkyl;

or two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9; or two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more Rs; or two R8 on the same carbon atom together form a (C3-C7) spirocycloalkyl ring, wherein the spirocycloalkyl ring is optionally substituted with one or more R9; or two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the

spiroheterocycloalkyl ring is optionally substituted with one or more R9;

each R9 is independently (d-d) alkyl, (d-d) haloalkyl, (d-d) alkoxy,

(d-d) haloalkoxy, (d-d) hydroxyalkyl, -OH, halogen, -CN, -NH₂, (d-d) alkylamino, or (d-d) dialkylamino; each R1o and R11 is independently H, (C1-C4) alkyl, (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C6) cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from (C1-C4) alkyl,

(C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH; or

R₁₀ and R11 together with the nitrogen atom to which they are attached form a

heterocycloalkyl ring optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, -OH, halogen, -NH2, (C1-C4) alkylamino, and (C1-C4) dialkylamino;

each R]₂ and R13 is independently H, (C1-C4) alkyl, or (C3-C7) cycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from CN, -NH2, -OH, and halogen;

q is 1 or 2; and

each m, n, o, and p is independently 0, 1, 2, or 3.

[0291] Embodiment Π-2. The compound of Embodiment Π-1, having Formula (Id-X):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. [0292] Embodiment II-3. The compound of Embodiment II- 1, having Formula (Ie-Χ) or (If- X):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0293] Embodiment Π-4. The compound of Embodiment Π- 1 , having Formula (Ii-X):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof. [0294] Embodiment II-5. The compound of Embodiment II-l, having Formula (lj-X):

(Ij-X),

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0295] Embodiment Π-6. The compound of Embodiment II-l selected from the group consisting of:

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2 -amine;

7-(4-amino-l-piperidyl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,8-diazaspiro[4.5]decan-8-yl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[4-(aminomethyl)-l-piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[3-(aminomethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

[l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3-yl]methanol;

l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidine-3-carboxamide; l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3-(aminomethyl)pyrrolidin-3-ol;

7- [3 -(aminomethy l)-3 -fluoro-pyrrolidin- 1 -y 1] -6-(2, 6-dichlorophenyl)pyrido[2, 3-d] pyrimidin-2- amine;

7-[3-(l-aminoethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine; 6-(2,6-dichlorophenyl)-7-[4-(methylaminomethyl)-l-piperidyl]pyrido[2,3-d]pyrimidin-2-amine; 7-[3-(l-aminoethyl)azetidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7- [4-( 1 -aminoethy 1)- 1 -piperidyl] -6-(2,6-dichlorophenyl)pyrido[2, 3-d] pyrimidin-2-amine;

7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-b]pyrrol-5-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine;

3 - [ [ 1 - [2-amino-6-(2,6-dichlorophenyl)py rido[2, 3-d] pyrimidin-7-yl]pyrrolidin-3 - yl]methylamino]propanenitrile;

2-(((l-(2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3- yl)methyl)amino)ethan- 1 -ol;

7-[3-[(cyclopropylamino)methyl]pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidi 2-amine;

6- (2,6-dichlorophenyl)-7-[3-[(2,2-difluoroethylamino)methyl]pyrrolidin-l-yl]pyrido[2,3- d]pyrimidin-2-amine;

[3-amino-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yl]methanol;

[(3R,4R)-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-4- (hydroxymethyl)pyrrolidin-3-yl]methanol;

7- (3 -aminopyrrolidin- 1 -yl)-6-( 1 -naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(3-aminoazetidin-l-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3J^]hexan-3-yl)-6-(l-mphthyl)pyrido[2,3-d]pyrimidm-2- amine;

7-(2,8-diazaspiro[4J]decan-8-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,7-diazaspiro[3.5]nomn-7-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-c]pyrrol-5-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidm 2-amine;

7-[3-(aminomethyl)azetidin-l -yl]-6-(l -naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

6-(l-naphthyl)-7-piperazin-l-yl-pyrido[2,3-d]pyrimidin- 2-amine; 7-(3-aminoazetidin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-ami

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(5-fluoro-6-methoxy-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methyl-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

2-[4-[2-[2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyrido[2,3-d]pyrimidin-

6- yl]-3-chloro-phenyl]pyrazol- 1 -yl]acetic acid;

7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methoxy-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methylthiazol-5- yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-(6-ethoxy-3 - pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6- [6-(dimethy lamino)-3 - pyridyl]phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(4-pyridyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-methyl-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-( 1 -methylpyrazol-4- yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-(6-methoxy-3 - pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

N-[5-[2-[2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-

6- yl]-3-chloro-phenyl]-2-pyridyl]methanesulfonamide;

7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine; 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-isobutoxy- phenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6- (cyclopropylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-methoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-bromo-6-methoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(te1rahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3J.0]hexan-3-yl]-6-[2-chloro-6-(te1rahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

2- [2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-6-yl^

3- chloro-phenoxy]acetic acid;

4- [2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-6-yl^ 3-chloro-phenoxy]butanoic acid;

7- [(3R)-3 -(aminomethy l)pyrrolidin- 1 -yl] -6-(2-chloro-6-isobutoxy-phenyl)pyrido[2, 3 - d]pyrimidin-2-amine;

7- [(3 S)-3 -(aminomethyl)pyrrolidin- 1 -yl] -6-(2-chloro-6-isobutoxy-phenyl)pyrido [2,3 - d]pyrimidin-2-amine;

7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine;

7-(4-methylpiperazin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine; 6-(2-ethoxyphenyl)-7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)pyrido[2,3-d]pyrimidin-2-

6-(2-ethoxypheny l)-7-(4-methy lpiperazin- 1 -yl)pyrido[2,3 -d]pyrimidin-2-amine; and

6-(2-chloro-6-isobutoxy-phenyl)-7-[3-(5-fluoro-2-methyl-anilino)pyrrolidin-l-yl]pyrido[2,3- d]pyrimidin-2-amine;

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

[0296] Embodiment II-7. A pharmaceutical composition comprising a compound of any one of Embodiments Π-1 to II-6 and a pharmaceutically acceptable carrier.

[0297] Embodiment II-8. A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of Embodiments Π-1 to Π-6.

[0298] Embodiment Π-9. A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to Embodiment Π-7.

[0299] Embodiment 11-10. The method according to Embodiment Π-8 or Π-9, wherein said bacterial infection is a gram-negative bacterial infection.

[0300] Embodiment II- 11. The method according to Embodiment Π-10, wherein said gram- negative bacterial infection is Pseudomonas aeruginosa, Stenotrophomonas maltophila,

Burkholderia cepacia, Alcaligenes xylosoxidans, Enter obacteriaceae, Haemophilus,

Acinetobacter, Franciscellaceae or a Neisseria species.

[0301] Embodiment 11-12. The method according to Embodiment II-8 or II-9, wherein said bacterial infection is a gram-positive bacterial infection.

[0302] Embodiment 11-13. The method according to Embodiment 11-12, wherein said gram- positive bacterial infection is Staphylococcus, Streptococcus, Enterococcus, Bacillus,

Clostridium, or a Listeria species.

Examples

[0303] The disclosure is further illustrated by the following examples and synthesis schemes, which are not to be construed as limiting this disclosure in scope or spirit to the specific procedures herein described. It is to be understood that the examples are provided to illustrate certain embodiments and that no limitation to the scope of the disclosure is intended thereby. It is to be further understood that resort may be had to various other embodiments, modifications, and equivalents thereof which may suggest themselves to those skilled in the art without departing from the spirit of the present disclosure and/or scope of the appended claims.

Analytical Methods, Materials, and Instrumentation

[0304] Unless otherwise noted, reagents and solvents were used as received from

commercial suppliers. Analytical LCMS was conducted on an Agilent 1200 series UPLC coupled with an Agilent G1946D Mass spectrometer and an Agilent 1200 DAD UV detector. (Column: Agilent SB-C18 RRHD 1.8 μιη; 2.1 x 50 mm; Flow rate 0.8 mL/min; Solvent A (0.1% TFA in water), Solvent B (0.1% TFA in acetonitrile); column temperature 35 °C.

[0305] LC retention times are based on the following methods: HPLC Method 1 : Gradient: 2-50% eluent B over 2.0 minutes; HPLC Method 2: Gradient: 2-99% eluent B over 2.0 minutes; and HPLC Method 3: Gradient: 2-30% eluent B over 2.0 minutes. Mass spectrometry parameters were as follows: Capillary voltage: 2500V; Fragmentor/Gain: 100; Gain: 1.0; Drying gas flow: 12.5 L/min; Gas Temperature: 350 °C; Nebulizer Pressure: 60 psig; Scan Range: 100- 1000 amu.

[0306] Abbreviations used in the following examples and elsewhere herein are:

ACN acetonitrile

AcOH acetic acid

arm atmosphere

br broad

d doublet

DCM dichloromethane

DMF N,N-dimethylforrnamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

ESI electrospray ionization

h hour(s)

HATU [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-0]pyridinium 3-

RT room temperature

s singlet

SPhos 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl

t triplet

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin layer chromatography

UV ultraviolet

Example 1: 7-f(lR,5S, 6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2,6-dichlorophenyl) pyrido[2,3-d]pyrimidin-2-amine (1-1)

Step 1. 6-(2,6-dichlorophenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-anmie (l-3a).

[0307] 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (l-2a) (3.1 g, 18 mmol) was dissolved in 40 rtiL anhydrous dimethylformamide and cooled in an ice/methanol bath (-10 °C) for 15 minutes under an atmosphere of nitrogen. Sodium hydride (0.73 g, 18 mmol) divided into 5 portions was added over the course of 5 minutes keeping the reaction mixture cooled with stirring. After an additional 5 minutes, a solution of 2,6-dichlorobenzylacetonitrile (1-la) (4.9 g, 27 mmol) in 12 mL anhydrous dimethylformamide was added drop wise via syringe. The resulting mixture was stirred at -10 °C for 30 minutes then allowed to warm to room temperature overnight after which time the reaction mixture was cooled in an ice bath and slowly quenched with 50 mL saturated NEUCl. After stirring for 20 minutes the product was extracted into DCM. The combined DCM extracts were dried over MgSCk, filtered, and concentrated under reduced pressure. The residue was re-dissolved in ethyl acetate and washed with brine. The organic layer was filtered through a sintered glass funnel and the filtrate was dried over sodium sulfate, filtered, and concentrated under reduced pressure to dryness. The residue was purified by silica gel chromatography eluting with ethyl acetate/dichloromethane to afford 708 mg (11%) 6-(2,6- dichlorophenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-amine (l-3a). LCMS (ESI):

[M+H]^÷ = 336.9.

Step 2. 6-(2,6-dichlorophenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (l-4a).

[0308] 6-(2,6-dichlorophenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-amine (l-3a) (200 mg, 0.60 mmol) was dissolved in trifluoroacetic acid (5 mL) and cooled in an ice bath. Sodium nitrite (110 mg, 1.6 mmol) was added and the reaction was stirred in the bath for 15 minutes, then at room temperature for 2.5 h, after which time the reaction was slowly added to a mixture of Na₂C0₃, saturated aqueous sodium bicarbonate and ice (15-20 mL). The product was extracted with ethyl acetate (2 x 15 mL) and the combined organic layers were dried with sodium sulfate, filtered, and concentrated under vacuum giving 194 mg (96%) of 6-(2,6-dichlorophenyl)- 2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (l-4a). LCMS (ESI): [M+H]⁺= 338.0.

Step 3. 7-chloro-6-(2,6-dichlorophenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (l-5a).

[0309] 6-(2,6-dichlorophenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (l-4a) (190 mg, 0.57 mmol) was combined with POCh (1.1 mL, 11 mmol) and dimethylformamide (1.0 μΐ,) at room temperature. The reaction was heated at 95 °C. An additional charge of POCb (1.1 mL, 11 mmol) was then added after 5 min. After 2 h, POCh was removed by concentrating the reaction mixture under reduced pressure. Ice and cold water were added to the resulting residue to obtain a solid that was collected by filtration and rinsed with water. After drying the resulting solid under vacuum, 195 mg (96%) of 7-chloro-6-(2,6-dichlorophenyl)-2-methylsulfanyl- pyrido[2,3-d]pyrimidine (l-5a) was obtained. LCMS (ESI): [M+H]⁺= 356.0. Step 4. tert-buty\ iV-[3-[6-(2,6-dichloropheiiyl)-2-methylsuIfanyl-pyrido[2,3-d]pyrimidin-7- yl] -3-azabicyclo [3.1.0] hexan-6-yI] carbamate ( l-7a).

[0310] To 7-chloro-6-(2,6-dichlorophenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (l-5a) (35 mg, 0.10 mmol) was added acetonitrile (0.30 mL) 1,4-dioxane (0.30 mL), tert-butyl N-(3- azabicyclo[3.1.0]hexan-6-yl)carbamate (l-6a) (21 mg, 0.11 mmol) and N,N"- diisopropylethylamine (0.03 mL, 0.20 mmol) and the resulting mixture was heated to 80 °C, Additional portions of diisopropylethylamine and tert-butyl N-(3-azabicyclo[3.1.0]hexan-6- yl)carbamate were then added and the temperature of the reaction mixture was increased to 90 °C. After heating overnight, the solvent was removed by concentration under reduced pressure. The resulting residue was dissolved in DCM (1 mL) and the organic layer was washed with 1M citric acid (2 x 1 mL), water, and saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 66 mg of crude tert-butyl N- [3-[6-(2,6-dichlorophenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-yl]-3- azabicyclo[3.1.0]hexan-6-yl]carbamate (l-7a), which was used in the next step without further purification. LCMS (ESI): [M+H]^÷ = 518.1.

Step 5. tert-butyl iV-[3-[6-(2,6-dichlorophenyl)-2-methylsuIfinyl-pyrido[2,3-d]pyrimidin-7- yl] -3-azabicyclo [3.1.0] hexan-6-yl] carbamate ( l-8a).

[0311] To tert-butyl N-[3-[6-(2,6-dichlorophenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin- 7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (l-7a) (51 mg, 0.10 mmol) in DCM (1 mL) was added 3-chloroperbenzoic acid (15 mg, 0.090 mmol) at room temperature. After 2 h, the reaction mixture was washed with saturated aqueous sodium bicarbonate, dried with sodium sulfate, filtered, and concentrated under reduced pressure to yield 60 mg of crude tert-butyl N-[3- [6-(2,6-dichlorophenyl)-2-methylsulfinyl-pyrido[2,3-d]pyrimidin-7-yl]-3- azabicyclo[3.1.0]hexan-6-yl]carbamate (l-8a) which was taken forward without further purification. LCMS (ESI): [M+H]^÷ = 534.0.

Step 6. tert-butyl iV-[3-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidm-7-yl]-3- azabicyclo[3.1.0]hexan-6-yl]carbamate (l-9a).

[0312] tert-butyl N-[3-[6-(2,6-dichlorophenyl)-2-methylsulfinyl-pyrido[2,3-d]pyrimidin-7- yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (l-8a) (52 mg, 0.10 mmol) was dissolved in THF (2 mL) and ammonia (5 M in MeOH) (0.49 mL, 2.5 mmol) at rt and the resulting mixture was heated to 65 °C for 15 h. The reaction mixture was then concentrated to provide crude tert-butyl N- [3 - [2-amino-6-(2, 6-dichlorophenyl)pyrido [2,3 -d] pyrimidin-7-yl] -3 -azabicy clo[3.1.0] hexan-6- yl]carbamate (l-9a) as an oil, which was used in the next step without further purification.

LCMS (ESI): [M+H]^÷= 487.0.

Step 7. 7- [(lR,5S,6s)-6-amino-3-azabicyclo [3.1.0] hexan-3-yl)-6-(2,6-dichlorophenyl) pyrido[2,3-d]pyriniidin-2-amine (1-1).

[0313] tert-butyl N-[3-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3- azabicyclo[3.1.0]hexan-6-yl]carbamate (l-9a) (48 mg, 0.10 mmol) was dissolved in DCM (0.50 mL) and TFA (0.50 mL) at room temperature. After 45 minutes, the reaction was concentrated under reduced pressure. The resulting residue was dissolved in dimethylformamide and purified by reverse phase HPLC (1" Phenomenex Luna column, 0.1% TFA in water/ACN) to afford 18 mg (35% over four steps) 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2,6- dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (1-1). LCMS (ESI): [M+H]⁺= 387.0, HPLC retention time (method 1): 0.982 min.

Example 2: 7-(4-amino-l-piperidyl)-6-(2,6-dichlorophenyl)pyrido[2,3-d] pyrimidin-2-amine

(1-2)

[0314] 7-(4-amino-l-piperidyl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine (1-2) was prepared according to the method described in Example 1 from Boc-4-aminopiperidine (in Step 4). LCMS (ESI): [M+Hf = 389.0. HPLC retention time (method 1): 1.023 min. Example 3: 7-(2,8-diazaspiro[4.5jdecan-8-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- dJpyrimidin-2-amine (1-3)

[0315] 7-(2,8-diazaspiro[4.5]decan-8-yl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2- amine (1-3) was prepared according to the method described in Example 1 from tert-butyl 2,8- diazaspiro[4.5]decane-2-carboxylate (in Step 4) and 2-(benzenesulfonyl)-3-phenyl-oxaziridine (39-4) (in Step 5). LCMS (ESI): [M+H]⁺ = 429.0, HPLC retention time (method 1): 1.121 min.

Example 4: 7-[4-(aminomethyl)-l-piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin- 2-amine (1-4)

[0316] 7-[4-(aminomethyl)-l-piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2- amine (1-4) was prepared according to the method described in Example 1 from tert-butyl N-(4- piperidinylmethyl)carbamate (in Step 4) and 2-(benzenesulfonyl)-3-phenyl-oxaziridine (39-4) (in Step 5). LCMS (ESI): [M+H]^÷ = 403.0. HPLC retention time (method 1): 1.065 min. Example 5: 7-[3-(aminomethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- dJpyrimidin-2-amine (1-5)

.CI

[0317] 7-[3-(aminomethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2- amine (1-5) was prepared according to the method described in Example 1 from 3-(N-Boc- Aminomethyl)pyrrolidone in Step 4 and using gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺= 389.0. HPLC retention time (method 1): 1.023 min.

Example 6: [1- [2-amino-6-(2,6-dichlorophenyl)pyrido [2,3-d] pyrimidin-7-yl] pyrrolidin-3- yl] methanol (1-6)

.CI

[0318] [l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yljmethanol (1-6) was prepared according to the method described in Example 1, Steps 1-6 from pyrrolidin-3-ylmethanol in Step 4 and using gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺= 390.0. HPLC retention time (method 1): 1.344 min. Example 7: l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-dJpyrimidin-7-yljpyrrolidine-3- carboxamide (1-7)

[0319] l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidine-3- carboxamide (1-7) was prepared according to the method described in Example 1, Steps 1-6 from pyrrolidine-3-carboxamide hydrochloride in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺ = 403.3. HPLC retention time (method 1): 1.217 min.

Example 8: l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3- (aminomethyl)pyrrolidin-3-ol (1-8)

[0320] l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3- (aminomethyl)pyrrolidin-3-ol (1-8) was prepared according to the method described in Example 1 from fert-butyl N-[(3-hydroxypyrrolidin-3-yl)methyl]carbamate in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺= 405.0. HPLC retention time (method 1): 0.975 min. Example 9: 7-[3-(aminomethyI)-3-fluoro-pyrrolidiii-l-yl]-6-(2,6-dichlorophenyl) pyrido[2,3-d]pyriniidin-2-amine (1-9)

[0321] 7-[3-(aminomethyl)-3-fluoro-pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine (1-9) was prepared according to the method described in Example 1 from fert-butyl N-[(3-fluoropyrrolidin-3-yl)methyl]carbamate in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺= 405.0. HPLC retention time (method 1): 0.975 min.

Example 10: 7-[3-(l-aminoethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- dJpyrimidin-2- amine (diastereomer A) (1-10)

•CI

[0322] 7-[3-(l-aminoethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2- amine (diastereomer A) (1-10) was prepared according to the method described in Example 1 from tert-butyl N-(l-pyrrolidin-3-ylethyl)carbamate (10-4a) in step 4 and gaseous ammonia instead of 5 M ammonia in methanol in step 6. LCMS (ESI): [M+H]⁺= 403.0. HPLC retention time (method 1): 1.016 min. Example 11: 7-[3-(l-aminoethyI)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- dJpyrimidin-2-amine (diastereomer B) (I- 11)

[0323] 7-[3-(l-aminoethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2- amine (diastereomer B) (I- 11) was prepared according to the method described in Example 1 from tert-butyl iV-(l-pyrrolidin-3-ylethyl)carbamate (10-4b) in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]^÷ = 403.0. HPLC retention time (method 1): 1.067 min.

Example 12: 6-(2,6-dichlorophenyl)-7-[4-(methylaminomethyl)-l-piperidyl]pyrido[2,3- d]pyrimidin-2-amine (1-12)

[0324] 6-(2,6-dichlorophenyl)-7-[4-(methylaminomethyl)-l-piperidyl]pyrido[2,3- d]pyrimidin-2-amine (1-12) was prepared according to the method described in Example 1 from tert-butyl N-methyl-N-(4-piperidylmethyl)carbamate in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺= 417.0. HPLC retention time (method 1): 1.053 min. Example 13: 7-[3-(l-aminoethyl)azetidiii-l-yl]-6-(2,6-dichIorophenyl)pyrido[2,3- dJpyrimidin-2-amine (1-13)

[0325] 7-[3-(l -aminoethyl)azetidin- 1 -yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2- amine (1-13) was prepared according to the method described in Example 1 from tert-butyl N-[l- (azetidin-3-yl)ethyl]carbamate in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺= 389.0. HPLC retention time (method 1): 0.910 min.

Example 14: 7-[4-(l-aminoethyl)-l-piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine (1-14)

[0326] 7-[4-(l-aminoethyl)-l-piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2- amine (1-14) was prepared according to the method described in Example 1 from tert-butyl N-[l- (4-piperidyl)ethyl] carbamate in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺ = 417.0. HPLC retention time (method 1): 1.065 min. Example 15: 7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-b]pyrrol-5-yl)-6-(2,6- dichlorophenyl)py rido [2,3-d] py rimidin-2-amine (I- 15)

[0327] 7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-b]pyrrol-5-yl)-6-(2,6-dichlorophenyl) pyrido[2,3-d]pyrimidin-2-amine (1-15) was prepared according to the method described in Example 1 from tert-butyl 3,3a,4,5,6,6a-hexahydro-2H-pyrrolo[2,3-c]pyrrole-l-carboxylate in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]^÷ = 401.1. HPLC retention time (method 1): 0.959 min.

Example 16: 3-[[l-[2-amiiio-6-(2,6-dichloropheiiyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin- 3-yl] methylamino] propaiienitrile (I- 16)

[0328] 3-[[l -[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yl]methylamino]propanenitrile (1-16) was prepared according to the method described in Example 1 from tert-butyl N-(2-cyanoethyl)-N-(pyrrolidin-3-ylmethyl)carbamate (16-4) in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺ = 442.0. HPLC retention time (method 1): 1.063 min. Example 17: bitermediate- tert- butyl iV-(2-cyaiioethyl)-N-(pyrrolidiii-3-ylmethyl) carbamate (16-4)

Step 1. Benzyl 3-[(2-cyanoethylamino)methyl]pyrrolidine-l-carboxylate (16-2).

[0329] Benzyl 3-formylpyrrolidine- 1 -carboxylate (16-1) (250 mg, 1.1 mmol) and 3- aminopropanenitrile (0.080 mL, 1.2 mmol) were combined in DCM (1.6 niL) and methanol (1.6 raL). After stirring for 10 min, the reaction was cooled in an ice bath and sodium

cyanoborohydride (79 mg, 1.3 mmol) was then added followed by the dropwise addition of trifluoroacetic acid (0.10 mL, 1.3 mmol). After 30 min, the reaction was diluted with DCM (0.5 mL) and the product was extracted into 0.5 M citric acid (3 x 2 mL). The pH of the combined aqueous layers was adjusted to >8 with solid K CO3 and then the product was extracted with MTBE (2 x 3 mL) and the combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 183 mg (61%) crude benzyl 3-[(2- cyanoethylamino)methyl]pyrrolidine-l -carboxylate LCMS (ESI): [M+H]⁺= 288.1.

Step 2. Benzyl 3-[[i'eri'-butoxycarbonyl(2-cyanoethyl)amino]methyl]pyrrolidine-l- carboxylate (16-3).

[0330] Benzyl 3-[(2-cyanoethylamino)methyl]pyrrolidine-l -carboxylate (16-2) (180 mg, 0.64 mmol), N,N"-diisopropylethylamine (0.13 mL, 0.76 mmol) and di-tert-butyldicarbonate (0.16 mL, 0.70 mmol) were combined in DCM (3 mL) and the resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with N,N-dimethyl-l,3- propanediamine (0.04 mL, 0.32 mmol) and then washed with 1 M citric acid (2 x 2 mL), water, saturated aqueous sodium bicarbonate (1 x 2 mL), and brine, dried with sodium sulfate, filtered, and concentrated to give 184 mg (75%) of benzyl 3-[[tert-butoxycarbonyl(2- cyanoethyl)amino]methyl]pyrrolidine-l-carboxylate (16-3). The product was carried onto the next step without further purification. LCMS (ESI): [M+Na]⁺= 410.1.

Step 3. tert-butyl iV-(2-cyanoethyl)-N-(pyrrolidiii-3-ylmethyl)carbamate (16-4).

[0331] To benzyl 3-[[tert-butoxycarbonyl(2-cyanoethyl)amino]methyl]pyrrolidine-l- carboxylate (180 mg, 0.47 mmol) (16-3) in methanol (4 mL) was added Pd/C (20%, eggshell, wet) (30 mg, 0.47 mmol) and the resulting mixture was stirred under a hydrogen atmosphere for 2 days. Two additional portions of Pd/C were then added over the 2 days. The reaction mixture was filtered to remove the Pd/C and the filtrate was concentrated under reduced pressure to give 106 mg (88%) of tert-butyl N-(2-cyanoethyl)-N-(pyrrolidin-3-ylmethyl)carbamate (16-4).

LCMS (ESI): [M+H]^÷= 254.1.

Example 18: 2-(((l-(2-amino-6-(2,6-dichlorophenyl)pyrido [2,3-d] pyrimidin-7- yl)pyrrolidin-3-yl)methyl)amino)ethan-l-ol (1-17)

O

[0332] 2-(((l-(2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3- yl)methyl)amino)ethan-l-ol (1-17) was prepared according to the method described in Example 1 from tert-butyl N-(2-hydroxyethyl)-N-(pyrrolidin-3-ylmethyl)carbamate (17-1) in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺ = 433.0. HPLC retention time (method 1): 1.026 min.

Example 19: bitermediate- tert- butyl iV-(2-hydroxyethyl)-iV-(pyrroIidin-3-yImethyl) carbamate (17-1)

[0333] fc?/t-butyl N-(2-hydroxyethyl)-N-(pyrrolidin-3-ylmethyl)carbamate (17-1) was prepared according to the method used for intermediate 16-4 (Example 17) from

hydroxy ethylamine in Step 1.

Example 20: 7- [3- [(cyclopropylamino)methyl] pyrrolidin- 1-yl] -6-(2,6- dichlorophenyl)py rido [2,3-d] py rimidin-2-amine (I- 18)

.CI

[0334] 7-[3-[(cyclopropylamino)methyl]pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine (1-18) was prepared according to the method described in Example 1 from tert-butyl N-cyclopropyl-N-(pyrrolidin-3-ylmethyl)carbamate (18-1) in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺= 429.4. HPLC retention time (method 1): 1.122 min.

Example 21: Intermediate- tert-butyl N-cyclopropyl-N-(pyrrolidin-3-ylmethyl)carbamate

(18-1)

[0335] tert-butyl N-cyclopropyl-iV-(pyrrolidin-3-ylmethyl)carbamate (18-1) was prepared according to the method used for intermediate 16-4 (Example 17) from cyclopropylamine in Step 1.

Example 22: 6-(2,6-dichlorophenyl)-7- [3- [(2,2-difluoroethylamino)methyl] pyrrolidin- 1- yl] pyrido [2,3-dJ pyrimidin-2-amine (I- 19)

[0336] 6-(2,6-dichlorophenyl)-7-[3-[(2,2-difluoroethylamino)methyl]pyrrolidin-l- yl]pyrido[2,3-d]pyrimidin-2-amine (1-19) was prepared according to the method described in Example 1 from tert-butyl N-(2,2-difluoroethyl)-N-(pyrrolidin-3-ylmethyl)carbamate (19-1) in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]^÷ = 453.3. HPLC retention time (method 1): 1.087 min.

Example 22: Intermediate i tert-buty jlV-(2,2-difluoroethyl)-N-(pyrrolidin-3- ylmethyl)carbamate (19-1)

[0337] tert-buty Nl -(2,2-difluoroethyl)-N-(pyrrolidin-3-ylmethyl)carbamate (19-1) was prepared according to the method described for intermediate (16-4) using 2,2-difluoroethylamine in Step 1. Example 23: [3-amino-l- [2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d] pyrimidiii-7- yl]pyrroIidin-3-yl] methanol (1-20)

•CI

[0338] [3-amino- 1 -[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin- 3-yl]methanol (1-20) was prepared according to the method described in Example 1 from tert- butyl N-[3-(hydroxymethyl)pyrrolidin-3-yl]carbamate in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]⁺= 405.3. HPLC retention time (method 1): 0.943 min.

Example 24: [(3R,4R)- 1- [2-amino-6-(2,6-dichlorophenyl)pyrido [2,3-d] pyrimidin-7-yl]-4- (hydroxymethyl)pyrrolidin-3-yl]methanol (1-21)

[0339] [(3R,4R)-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-4- (hydroxymethyl)pyrrolidin-3-yl] methanol (1-21) was prepared according to the method described in Example 1 from [(3R,4R)-4-(hydroxymethyl)pyrrolidin-3-yl]methanol and DMSO as solvent in Step 4 and gaseous ammonia instead of 5 M ammonia in methanol in Step 6. LCMS (ESI): [M+H]^÷ = 420.0. HPLC retention time (method 1): 1.141 min. Example 25: 7-(3-aminopyrrolidin-l-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine (I-

Step 1. 2-methylsulfanyl-6-(l-iiaphthyl)-8H-pyrido[2,3-d]pyriniidin-7-one (22-2).

[0340] 6-Bromo-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (1.0 g, 3.8 mmol) (22- 1), 1-naphthylboronic acid (1.3 g, 7.6 mmol), potassium fluoride (0.67 g, 11 mmol), 1,4-dioxane (30 mL), methanol (9 niL), Pd₂(dba)₃ (70 mg, 0.080 mmol), and dicyclohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane (31 mg, 0.080 mmol) (SPhos) were combined and the resulting mixture was heated to 95 °C in a heating block. After 2 h, the reaction mixture was concentrated under reduced pressure to a slurry and then dissolved in DCM. The material was filtered and the filtrate was purified by silica gel chromatography eluting with hexanes/MTBE to afford 665 mg (55%) 2-methylsulfanyl-6-(l-naphthyl)-8H-pyrido[2,3-d]pyrimidin-7-one (22-2). LCMS (ESI): [M+H]^÷= 320.0.

Step 2. 7-chloro-2-methylsulfanyl-6-(l-naphthyl)pyrido[2,3-d]pyrimidine (22-3).

[0341] 2-Methylsulfanyl-6-(l-naphthyl)-8H-pyrido[2,3-d]pyrimidin-7-one (670 mg, 2.1 mmol) (22-2), POCh (3.8 mL, 41 mmol), and DMF (1 nL) were combined and the resulting mixture was heated at 95 °C. After 2 h, POCh was removed by concentrating the mixture under reduced pressure. Cold water was added to the resulting residue and the resulting solid was collected by filtration and rinsed with water. After drying under reduced pressure, 500 mg (71%) of 7-chloro-2-methylsulfanyl-6-(l-naphthyl)pyrido[2,3-d]pyrimidine (22-3) was obtained. LCMS (ESI): [M+H]^÷= 338.0. Step 3. tert-butyl iV-[l-[2-methylsulfanyl-6-(l-naphthyl)pyrido[2,3-dJpyi'imidin-7- yl] pyrroIidin-3-yl] carbamate (22-5).

[0342] To a suspension of 7-chloro-2-methylsulfanyl-6-(l -naphthyl)pyrido[2,3-d]pyrimidine (60 mg, 0.18 mmol) (22-3) in 1,4-dioxane (1 mL) was added N,iV"-diisopropylethylamine (0.09 mL, 0.53 mmol) and 3-N-boc-amino pyrrolidine (0.03 mL, 0.21 mmol) (22-4). The resulting mixture was stirred at 80 °C for 4 h during which time additional portions of N,N"- diisopropylethylamine and 3-N-boc-amino pyrrolidine (22-4) were added. The solvent was removed under reduced pressure and the resulting residue was dissolved in DCM and the organic layer was washed with 1M citric acid, water, saturated aqueous sodium bicarbonate and brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 81 mg (94%) of tm-bu1yl iV-[l-[2-methylsulfanyl-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yl]carbamate (22-5). LCMS (ESI): [M+H]^÷= 488.1.

Step 4. tert-butyl iV-[l-[2-methylsulfonyl-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-7- yl] pyrrolidin-3-yl] carbamate (22-6).

[0343] tert-Butyl N-[l- [2-methy lsulfonyl-6-( 1 -naphthyl)pyrido [2,3 -d]pyrimidin-7- yl]pyrrolidin-3-yl]carbamate (22-6) was prepared according to the procedure in Example 1, Step 5, from tert-butyl N-[l-[2-methylsulfanyl-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin- 3-yl]carbamate (22-5). LCMS (ESI): [M+H]^÷ = 504.1

Step 5. tert-butyl iV-[l-[2-amino-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yl] carbamate (22-7).

[0344] tert-Butyl N- [ 1 - [2-amino-6-( 1 -naphthyi)pyrido [2,3 -d]pyrimidin-7-yl] pyrrolidin-3 - yl] carbamate (22-7) was prepared according to the procedure in Example 1, Step 6 from tert- butyl N-[l-[2-memylsulfonyl-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yljcarbamate (22-6). LCMS (ESI): [M+H]^÷= 457.0

Step 6. 7-(3-aminopyrrolidin-l-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine (1-22).

[0345] 7-(3-Aminopyrrolidin-l-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine (1-22) was prepared according to the procedure in Example 1, Step 7 from tert-butyl iV-[l-[2-amino-6- (l-naphthyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3-yl]carbamate (22-7). LCMS (ESI):

[M+H]^÷ = 357.1. HPLC retention time (method 1): 1.144 min. Example 26: 7-(3-aminoazetidin-l-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine (I- 23)

H₂N

[0346] 7-(3-Aminoazetidin-l-yl)-6-(l -naphthyl)pyrido[2,3-d]pyrimidin-2-amine (1-23) was prepared according to the method described in Example 25 using 2-(benzenesulfonyl)-3-phenyl- oxaziridine in Step 4. LCMS (ESI): [M+H]^÷ = 343.0. HPLC retention time (method 1 ): 1.104 min.

Example 27: 7-[(lR,5S, 6s)-6-amino-3-azabicycIo[3.1.0]hexan-3-yl]-6-(l- naphthyI)pyrido[2,3-d] pyrimidin-2-amine (1-24)

[0347] 7-[(l R,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(l -naphthyl)pyrido[2,3- d]pyrimidin-2-amine (1-24) was prepared according to the method described in Example 25 using 2-(benzenesulfonyl)-3-phenyl-oxaziridine in Step 4. LCMS (ESI): [M+H]⁺= 369.3. HPLC retention time (method 1): 1.145 min. Example 28: 7-(2,8-diazaspiro[4.5Jdecan-8-yl)-6-(l-iiaphthyl)pyrido[2,3-d]pyriniidin-2- aniine (1-25)

[0348] 7-(2,8-diazaspiro[4.5]decan-8-yl)-6-(l-naphtnyl)pyrido[2,3-d]pyrimidin-2-amine (I- 25) was prepared according to the method described in Example 25 using 2-(benzenesulfonyl)-3- phenyl-oxaziridine in Step 4. LCMS (ESI): [M+H]^÷= 411.1. HPLC retention time (method 1): 1.308 min.

Example 29: 7-(2,7-diazaspiro [3.5] nonan-7-yl)-6-( l-naphthyl)pyrido [2,3-d] py rimidiii-2- amine (1-26)

HN^J

[0349] 7-(2,7-diazaspiro[3.5]nonan-7-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine (I- 26) was prepared according to the method described in Example 25 using 2-(benzenesulfonyl)-3- phenyl-oxaziridine in Step 4. LCMS (ESI): [M+H]^÷= 397.1. HPLC retention time (method 1): 1.260 min. Example 30: 7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-cJpyrrol-5-yl)-6-(l- naphthyI)pyrido[2,3-dJ pyrimidin-2-amine (1-27)

[0350] 7-(2,3,3a,4,6,6a-hexahydro- lH-pyrrolo[3,4-c]pyrrol-5-yl)-6-(l -naphthyl)pyrido[2,3- d]pyrimidin-2-amine (1-27) was prepared according to the method described in Example 25 using 2-(benzenesulfonyl)-3-phenyl-oxaziridine in Step 4. LCMS (ESI): [M+H]⁺= 383.1.

HPLC retention time (method 1): 1.190 min.

Example 31: 7-[3-(aminomethyl)azetidin-l-yl]-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2- amine (1-28)

[0351] 7-[3-(aminomethyl)azetidin-l-yl]-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine (I- 28) was prepared according to the method described in Example 25 using 2-(benzenesulfonyl)-3- phenyl-oxaziridine in Step 4. LCMS (ESI): [M+H]^÷ = 357.1. HPLC retention time (method 1): 1.1 18 min. Example 32: 6-(l-naphthyl)-7-piperazin-l-yl-pyrido[2,3-dJpyrimidin-2-amine (1-29)

[0352] 6-(l -naphthyl)-7-piperazin- 1 -yl-pyrido[2,3-d]pyrimidin-2-amine (1-29) was prepared according to the method described in Example 25 using N-boc-piperazine in Step 3 and 2- (benzenesulfonyl)-3-phenyl-oxaziridine in Step 4. LCMS (ESI): [M+H]^÷ =357.3. HPLC retention time (method 2): 1.184 min.

Example 33: 7-(3-aminoazetidin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine (1-30)

Step 1. 6-Bromo-7-chloro-2-methylsulfanyl-pyrido[2,3-dJpyrimidine (30-1).

[0353] 6-Bromo-7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (30-1) was prepared according to the method described in Example 22, Step 1 from 6-bromo-2-methylsulfanyl-8H- pyrido[2,3-d]pyrimidin-7-one (22-l). LCMS (ESI): [M+H]⁺ = 289.8.

Step 2. tert- Butyl iV-[l-(6-bromo-2-methylsulfanyl-pyrido[2^-d]pyrimidin-7-yl)azetidin-3- yl] carbamate (30-3).

[0354] 6-Bromo-7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (280 mg, 0.96 mmol) and fcrt-butyl N-(azetidin-3-yi)carbamate hydrochloride (200 mg, 0.96 mmol) (30-2) were dissolved in dioxane (6 mL) and triethylamine (0.27 niL, 1.9 mmol) and the resulting mixture was heated to 85 °C for 30 min. The reaction mixture was cooled to room temperature and the resulting solids were collected by filtration. The solid was partitioned between water and EtOAc and the organic layer was dried with Na₂S0₄, filtered, and concentrated under reduced pressure to give 290 mg (72%) tert-butyl N-[l-(6-bromo-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7- yl)azetidin-3-yl]carbamate (30-3). LCMS (ESI): [M+H]^÷= 426.0.

Step 3. tert-Butyl N-[l- [2-methylsulfanyl-6- [2-(trifluoromethyl)phenyl] pyrido [2,3- d] pyrimidin-7-yl] azetidin-3-yl] carbamate (30-5).

[0355] To a suspension of fert-butyl iV-[l-(6-bromo-2-methylsulfanyl-pyrido[2,3- d]pyrimidin-7-yl)azetidin-3-yl]carbamate (140 mg, 0.33 mmol) (30-3), 2- trifluoromethylphenylboronic acid (125 mg, 0.66 mmol) (30-4) and KF (57 mg, 0.99 mmol) were suspended in 1,4-dioxane (2 mL), methanol (1 mL) and toluene (3 mL) under an atmosphere of nitrogen was added Pd₂dba₃ (15 mg, 0.020 mmol) and SPhos (6.7 mg, 0.020 mmol) and the resulting mixture was heated at 95 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove methanol and then purified by silica gel chromatography eluting with ethyl acetate/hexanes to afford 117 mg (72%) tert-butyl N-[l-[2- memylsulfanyl-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-7-yl]azetidin-3- yljcarbamate (30-5). LCMS (ESI): [M+H]^÷= 336.9. Step 4. tert- Butyl iV-[l-[2-methylsulfinyl-6-[2-(trifluoromethyI)phenyl]pyrido[2,3- d] pyrimidin-7-yl] azetidin-3-ylJ carbamate (30-6).

[0356] tert-Butyl N-[l-[2-methylsulfinyl-6-[2-(trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-7-yl]azetidin-3-yl]carbamate (30-6) was prepared according to the method described in Example 1, Step 5 from 2-(benzenesulfonyl)-3-phenyl-oxaziridine. LCMS (ESI): [M+H]⁺ = 508.0.

Step 5. tert- Butyl N- [1- [2-amino-6- [2-(trifiuoromethyI)pheiiyl] pyrido [2,3-d] pyrimidiii-7- yl] azetidiii-3-yl] carbamate (30- 7).

[0357] te/t-Butyl iV-[l-[2-amino-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-7- yl]azetidin-3-yl]carbamate (30-7) was prepared according to the method described in Example 1, Step 6 from 30-6. LCMS (ESI): [M+H]⁺= 461.1.

Step 6. 7-(3-aminoazetidin-l-yI)-6-[2-(trifluoromethyl)phenyI]pyrido[2,3-d]pyrimidin-2- amine (1-30).

[0358] 7-(3-aminoazetidin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2- amine (1-30) was prepared according to the method described in Example 1, Step 7 from 30-7. LCMS (ESI): [M+H]^÷= 361.0, HPLC retention time (method 1): 0.960 min.

Example 34: 7-[(lR,5S, 6s)-6-amino-3-azabicydo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(5-fluoro- 6-methoxy-3-pyridyI)phenyl] pyrido [2,3-d] pyrimidin-2-amine (1-31)

BocHN^'

Preparation of ferf-butyl N-[3-[2-amino-6-(2-bromo-6-chloro-phenyI)pyrido[2,3- d] pyrimidin-7-yl] -3-azabicyclo [3.1.0] hexan-6-yI] carbamate (31-1)

[0359] fcrt-Butyl N-[3- [2-amino-6-(2-br omo-6-chloro-phenyl)py rido[2, 3-d] pyrimidin-7-yl] - 3-azabicyclo[3.1.0]hexan-6-yl]carbamate (31-1) was prepared according to the methods described in Example 1, Steps 1-6, using 2-(2-bromo-6-chloro-phenyl)acetonitrile as the starting material in Step 1. LCMS (ESI): [M+H]⁺= 531.0.

Step 1. tert- Butyl iV-[3-[2-amiiio-6-[2-chloro-6-(5-fluoro-6-methoxy-3-pyridyl)pheiiyl] pyrido[2,3-d]pyriniidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (31-3).

[0360] tert-Butyl N- [3 - [2-amino-6-(2-bromo-6-chloro-phenyl)pyrido[2, 3-d] pyrimidin-7-yl] - 3-azabicyclo[3.1.0]hexan-6-yl]carbamate (15 mg, 0.030 mmol) (31-1), 1,4-dioxane (0.60 mL), sodium carbonate (1 M, 0.15 mL), (5-fluoro-6-methoxy-3-pyridyl)boronic acid (5.3 mg, 0.030 mmol) (31-2) and Pd(dppf)Cl₂ DCM complex (2.3 mg, 0.0028 mmol) were placed in a vial under an atmosphere of nitrogen at rt. The resulting mixture was heated to 100 °C for 1 h. The reaction mixture was extracted with EtOAc and the combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 20 mg of crude tert- butyl N-[3-[2-amino-6-[2-chloro-6-(5-fluoro-6-methoxy-3-pyridyl)phenyl]pyrido[2,3- d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (31-3) which was used in the next step without further purification. LCMS (ESI): [M+H]⁺= 578.1

Step 2. 7-f(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(5-fluoro-6- methoxy-3-pyridyl)phenyl] pyrido [2,3-d] pyrimidin-2-amine (1-31).

[0361] 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(5-fluoro-6- methoxy-3-pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-31) was prepared according to the method described in Example 1, Step 7 from 31-3. LCMS (ESI): [M+H]⁺= 478.0, HPLC retention time (method 1): 1.143 min.

Example 35: 7-[(lR,5S, 6s)-6-amino-3-azabicydo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2- methyl-4-pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amiiie (1-32)

[0362] 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methyl-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-32) was prepared according to the method described in Example 34 using 2-methyl-4-pyridineboronic acid in Step 1. LCMS (ESI):

[M+H]^÷ = 444.1. HPLC retention time (method 1): 0.731 min.

Example 36: 2-[4-[2-[2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3- yl]pyrido[2,3-d]pyrimidin-6-yl]-3-chloro-phenyl]pyrazol-l-yl]acetic acid (1-33)

[0363] 2-[4-[2-[2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3- d]pyrimidin-6-yl]-3-chloro-phenyl]pyrazol-l-yl]acetic acid (1-33) was prepared according to the method described in Example 34 using ethyl 2-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyrazol-l-yl]acetate in Step 1, except that the during the workup the aqueous layer was acidified with acetic acid to protonate the carboxylic acid which formed under the reaction conditions . LCMS (ESI): [M+H]⁺= 477.1. HPLC retention time (method 1): 0.984 min.

Example 37: 7-[(lR,5S, 6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-ylJ-6-[2-chloro-6-(2- methoxy-4-pyridyl)phenyl] pyrido [2,3-d] pyrimidin-2- amine (1-34)

[0364] 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methoxy-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-34) was prepared according to the method described in Example 34 using 2-methoxy-4-pyridineboronic acid in Step 1. LCMS (ESI): [M+H]^÷= 460.0. HPLC retention time (method 1): 1.031 min.

Example 38: 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0Jhexan-3-yl]-6-[2-chloro-6-(2- methylthiazol-5-yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-35)

[0365] 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2- methylthiazol-5-yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-35) was prepared according to the method described in Example 34 using 2-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)thiazole in Step 1. LCMS (ESI): [M+H]⁺ = 450.0, HPLC retention time (method 1): 0.994 min.

Example 39: 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-ethoxy-3- pyridyl)phenyl] pyrido [2,3-d] pyriniidiii-2-amine (1-36)

H

[0366] 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-ethoxy-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-36) was prepared according to the method described in Example 34 using 6-ethoxy-3-pyridineboronic acid in Step 1. LCMS (ESI):

[M+Hp = 474.1, HPLC retention time (method 1): 1.154 min.

Example 40: 7-f(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-[6- (dimethylamino)-3-pyridyl] phenyl] pyrido [2,3-d] pyrimidin-2-amine (1-37)

H [0367] 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-[6- (dimethylamino)-3-pyridyl]phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-37) was prepared according to the method described in Example 34 using 6-(dimethylamino)-3-pyridineboronic acid in Step 1. LCMS (ESI): [M+H]⁺= 473.1. HPLC retention time (method 1): 0.790 min.

Example 41: 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-ylJ-6-[2-chloro-6-(4- pyridyl)phenylj pyrido [2,3-d] pyrimidin-2-amiiie (1-38)

H

[0368] 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-38) was prepared according to the method described in Example 34 using 4-pyridineboronic acid in Step 1. LCMS (ESI): [M+H]⁺= 430.0. HPLC retention time (method 1): 0.740 min.

Example 42: 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-methyl- 3-pyridyl)phenyl] pyrido [2,3-d] pyrimidin-2-amine (1-39)

O..P see Example 1 ,

steps 1-4

Preparation of feri-butyl iV-[3-[6-(2-bromo-6-chloro-phenyl)-2-methylsulfanyl-pyrido[2,3- d] pyrimidin-7-yl] -3-azabicy clo [3.1.0J hexaii-6-yl] carbamate (39-1)

[0369] tert-Butyl N-[3-[6-(2-bromo-6-chloro-phenyl)-2-methylsulfanyl-pyrido[2,3- d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (39-1) was prepared according to the methods described in Example 1, Steps 1-4, from 2-(2-bromo-6-chloro-phenyl)acetonitrile in Step 1. LCMS (ESI): [M+H]⁺= 562.0.

Step 1. tert- Butyl iV-[3-[6-[2-chloro-6-(6-methyl-3-pyridyl)phenyl]-2-methylsulfaiiyl- pyrido[2,3-d]pyriniidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (39-3).

[0370] tert-Butyl N-[3-[6-[2-chloro-6-(6-methyl-3-pyridyl)phenyl]-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (39-3) was prepared according to the method described in Example 31, Step 1, from 6-methyl-3-pyridineboronic acid (39-2) as the starting material. LCMS (ESI): [M+H]^÷= 575.1.

Step 2. tert- Butyl iV-[3-[6-[2-chloro-6-(6-methyl-3-pyridyl)phenyl]-2-methylsulfinyI- pyrido[2,3-d]pyriniidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (39-5).

[0371] To fert-Butyl N-[3-[6-[2-chloro-6-(6-methyl-3-pyridyl)phenyl]-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (29 mg, 0.040 mmol) (39-3) in DCM (0.50 mL) was added 2-(benzenesulfonyl)-3-phenyl-oxaziridine (11 mg, 0.040 mmol) (39-4). The resulting mixture was stirred at rt for 1.5 h, and then concentrated under reduced pressure to give 50 mg of crude tert-butyl N-[3-[6-[2-chloro-6-(6-methyl-3- pyridyl)phenyl]-2-methylsulfinyl-pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6- yl] carbamate (39-5), which was used in the next step without further purification. LCMS (ESI): [M+H]^÷= 591.2.

Step 3. tert-Butyl N- [3- [2- Amino-6- [2-chloro-6-(6-methyl-3-pyridyl)phenyl] pyrido [2,3- d] pyrimidin-7-yl] -3-azabicy clo [3.1.0] hexan-6-yl] carbamate (39-6).

[0372] tert-Butyl N-[3-[6-[2-chloro-6-(6-methyl-3-pyridyl)phenyl]-2-methylsulfinyl- pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (25 mg, 0.040 mmol) (39-5) was dissolved in 1,4-dioxane (0.50 mL) and ammonia gas was bubbled into the reaction. The resulting mixture was placed into a heating block and heated to 60 °C for 13 h and then concentrated under reduced pressure to give 45 mg of tert-butyl N-[3-[2-amino-6-[2-chloro-6-(6- methyl-3-pyridyl)phenyl]pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (39-6), which was used in the next step without further purification. LCMS (ESI): [M+H]⁺ = 544.2.

Step 4. 7-[(lR,5S,6s)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-methyl-3- pyridyl)phenyl] pyrido [2,3-d] pyrimidiii-2-amine (1-39).

[0373] 7-[(lR,5S,6s)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-[2-chloro-6-(6-methyl-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-39) was prepared according to the method described in Example 1, Step 7 from 39-6. LCMS (ESI): [M+H]⁺= 444.1. HPLC retention time (method 1): 0.748 min.

Example 43: 7-[(lR,5S)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yI]-6-[2-chIoro-6-(l- methyIpyrazol-4-yl)phenyI] pyrido [2,3-d] py rimidin-2-amine (1-40)

H

[0374] 7-[(lR,5S)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(l-methylpyrazol- 4-yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-40) was prepared according to the method described for Example 42 using l-methyl-4-pyrazoleboronic acid in Step 1. LCMS (ESI):

[M+H]^÷ = 433.1. HPLC retention time (method 1): 1.014 min.

Example 44: 7- [( lR,5S)-6- Amino-3-azabicyclo [3.1.0] hexan-3-yI] -6- [2-chloro-6-(6-methoxy- 3-py ridyl)phenylj pyrido [2,3-d] pyrimidin-2-amiiie (1-41)

H

[0375] 7-[(lR,5S)-6-Amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-methoxy-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-41) was prepared according to the method described for Example 42 using 2-methoxy-5-pyridineboronic acid in Step 1. LCMS (ESI): [M+H]^÷ = 460.0. HPLC retention time (method 1): 1.109 min.

Example 45: iV-[5-f2-f2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclof3.1.0]hexan-3- yl)pyrido[2,3-d]pyrimidin-6-yl]-3-chloro-phenyl]-2-pyridyl]methanesulfonamide (1-42)

BocHN'

Preparation of feri-butyl iV-[3-[6-[2-(6-amino-3-pyridyl)-6-chIoro-pheiiyl]-2-methylsulfanyI- pyrido [2,3-d] pyriniidiii-7-yl] -3-azabicy clo [3.1.0] hexan-6-yl] carbamate (42- 1)

[0376] tert-butyl N-[3-[6-[2-(6-amino-3-pyridyl)-6-chloro-phenyl]-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (42-1) was prepared according to the method described in Example 39, Step 1, from 6-amino-3-pyridineboronic acid in Step 1. LCMS (ESI): [M+H]⁺ = 576.2.

Step 1. tert-butyl N- [3- [6- |2-chloro-6- [6-(methanesulfonamido)-3-pyridyI] phenyl] -2- methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl] -3-azabicy clo [3.1.0] hexan-6-yl] carbamate (42-

2) .

[0377] tert-butyl N-[3-[6-[2-(6-amino-3-pyridyl)-6-chloro-phenyl]-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (19 mg, 0.030 mmol) (42-1) and methanesulfonyl chloride (2.6 nL, 0.030 mmol) were combined in DCM (0.40 mL) and pyridine (0.10 mL) and the resulting mixture was stirred at rt for 20 h. Methanesulfonyl chloride (2.6 nL, 0.030 mmol) was then again added and the resulting mixture was heated to 30 °C for two days. The reaction mixture was diluted with DCM and the organic layer was washed with 1 M citric acid (2 X), saturated aqueous sodium bicarbonate and brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 15 mg (70%) of tert- butyl N-[3-[6-[2-chloro-6-[6-(methanesulf onamido)-3-pyridyl]phenyl]-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-yl]-3-azabic\xlo[3.1.0]hexan-6-yl]carbamate (42-2). LCMS (ESI): [M+H]^÷= 654.2.

Step 2. ieri-butyl N- [3- [6- [2-chloro-6- [6-(methanesulfonamido)-3-pyridyl] phenyl] -2- methylsulfinyl-pyrido [2,3-d] pyrimidin-7-yl] -3-azabicy clo [3.1.0] hexan-6-yl] carbamate (42-

3) .

[0378] tert-butyl N-[3-[6-[2-chloro-6-[6-(methanesulfonamido)-3-pyridyl]phenyl]-2- methylsulfinyl-pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (42-3) was prepared according to the method described in Example 1, Step 5 from 42-2. LCMS (ESI): [M+H]^÷ = 670.0. Step 3. tert-butyl N- [3- [2-amino-6- [2-chIoro-6- [6-(methanesulfonamido)-3- pyridyl] phenyl] pyrido [2,3-d] py rimidin-7-yl] -3-azabicy clo [3.1.0] hexan-6-yl] carbamate (42-

4).

[0379] tert-butyl N- [3 - [2-amino-6- [2-chloro-6- [6-(methanesulfonamido)-3 - pyridyl]phenyl]pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (42-4) was prepared according to the method described in Example 39, Step 3 from 42-3. LCMS (ESI): [M+H]^÷= 623.1

Step 4. JV-[5-[2-[2-ammo-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexaii-3-yl)pyrido[2,3- d] pyrimidin-6-yl] -3-chloro-pheiiyl] -2-pyridyl] methanesulfonamide (1-42).

[0380] N-[5-[2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyrido[2,3- d]pyrimidin-6-yl]-3-chloro-phenyl]-2-pyridyl]methanesulfonamide (1-42) was prepared according to the method described in Example 1, Step 7 from 42-2. LCMS (ESI): [M+Hp = 523.0. HPLC retention time (method 1): 0.933 min.

Example 46: 7-[(lR,5S,6s)-6-amiiio-3-azabicyclo[3.1.0]hexan-3-yl)-6-[2-chloro-6-(3- pyridyl)phenyl] pyrido [2,3-d] pyrimidiii-2-amine (1-43)

Step 1. 2-[2-Chloro-6-(3-pyridyl)phenyl]acetonitrile (43-3).

[0381] 2-(2-Bromo-6-chloro-phenyl)acetonitrile (450 mg, 2.0 mmol) (43-1), 3- pyridylboronic acid (251 mg, 2.1 mmol) (43-2), potassium fluoride (230 mg, 3.9 mmol), 1,4- dioxane (12 mL), methanol (3.6 mL), Pd₂(dba)₃ (71 mg, 0.080 mmol) and dicyclohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane (32 mg, 0.080 mmol) were combined under an atmosphere of nitrogen and the resulting mixture was heated at 80 °C. After 16 h, the reaction was filtered and concentrated under reduced pressure. The resulting oil was dissolved in DCM and purified by silica gel chromatography eluting with methanol/dichloromethane to afford 317 mg (71%) 2- [2-chloro-6-(3-pyridyl)phenyl]acetonitrile (43-3). LCMS (ESI): [M+H]^÷ = 229.1

Step 2. 6-[2-Chloro-6-(3-pyridyl)phenylJ-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-amine (43-4).

[0382] 2-[2-Chloro-6-(3-pyridyl)phenyl]acetonitrile (210 mg, 0.94 mmol) (43-3) was dissolved in DMF (3 mL) and THF (1.5 mL) and cooled in an ice bath. Sodium hydride (39 mg, 0.98 mmol) was added followed by 4-amino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (160 mg, 0.94 mmol) (1-2) and the resulting mixture was allowed to warm to rt overnight. The reaction mixture was then poured into ice and acidified to pH 4 with 10% aq. acetic acid. The resulting mixture was extracted with EtOAc (twice) and the combined organics were washed with water and brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was dissolved in DCM and purified by silica gel chromatography eluting with methanol/dichloromethane to afford 105 mg (30%) 6-[2-chloro-6-(3- pyridyl)phenyl]-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-amine (43-3). LCMS (ESI):

[M+H]^÷= 380.0.

Step 3. 6-[2-Chloro-6-(3-pyridyl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7- one (43-5).

[0383] To a solution of 6-[2-Chloro-6-(3-pyridyl)phenyl]-2-methylsulfanyl-pyrido[2,3- d]pyrimidin-7-amine (110 mg, 0.28 mmol) (43-4) in TFA (2 mL), cooled in an ice bath, was added sodium nitrite (52 mg, 0.75 mmol) and the resulting mixture was allowed to warm to rt. After stirring for 90 min, the reaction mixture was slowly added to a mixture of saturated sodium bicarbonate, solid sodium carbonate, and ice. The resulting mixture was extracted with EtOAc (twice) and the combined organics were washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 93 mg (88%) 6-[2-chloro-6-(3-pyridyl)phenyl]- 2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (43-5). The crude product was carried onto the next step without further purification. LCMS (ESI): [M+H]⁺= 381.0.

Step 4. 7-chIoro-6-[2-chloro-6-(3-pyridyl)phenylJ-2-methylsulfanyl-pyrido[2,3- d]pyrimidine (43-6).

[0384] 6-[2-chloro-6-(3-pyridyl)phenyl]-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (93 mg, 0.24 mmol) (43-5), POCh (0.89 niL, 9.8 mmol) and dimethyl formamide (1.9 μί, 0.020 mmol) were combined and heated to 95 °C in a heating block. After 4 h, the reaction was concentrated under reduced pressure and then further dried under high vacuum. The crude residue was dissolved in DCM and slowly added dropwise into ice cold saturated sodium bicarbonate. The layers were separated and the aqueous layer was extracted again with DCM. The combined organic layers were dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 68 mg (70%) 7-chloro-6-[2-chloro-6-(3-pyridyl)phenyl]-2- methylsulfanyl-pyrido[2,3-d]pyrimidine (43-6). The crude product was carried onto the next step without further purification. LCMS (ESI): [M+H]⁺= 399.0.

Steps 5-8. 7- [( lR,5S,6s)-6-amino-3-azabicyclo [3.1.0] hexan-3-yl)-6- [2-chloro-6-(3- pyridyl)phenyl] pyrido [2,3-d] pyrimidin-2-amine. (1-43)

[0385] Steps 5-8 were performed as described for Example 1, Steps 4-7 to give 17 mg of 7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-[2-chloro-6-(3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-43). LCMS (ESI): [M+H]+ = 430.0. HPLC retention time (method 1): 0.783 min.

Example 47 : 7- [( lR,5S,6s)-6-amino-3-azabicyclo [3.1.0] hexan-3-ylJ -6-(2-chloro-6-iso bu toxy- phenyl)py rido [2,3-d] py rimidin-2-amiiie (1-44)

Step 1. 2-Chloro-6-isobutoxy-benzaldehyde (44-2).

[0386] 2-Chloro-6-hydroxy-benzaldehyde (1.0 g, 6.4 mmol) and isobutyliodide (1.9 niL, 16 mmol) and potassium carbonate (1.3 g, 9.6 mmol) were combined in 8 mL of anhydrous DMF and the resulting mixture was heated at 90 °C in sealed vessel overnight. An additional isobutyl iodide was added and the heating was continued. The reaction mixture was cooled to room temperature and partitioned between water and EtOAc. The organic layer was washed with aqueous sodium metabisulfate, brine (3 X) and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford 932 mg (69%) 2-chloro-6-isobutoxy-benzaldehyde (44-2). LCMS (ESI): [M+H]⁺= 213.0.

Step 2. 2-(2-Chloro-6-isobutoxy-pheny])acetonitrile (44-4).

[0387] Potassium tert-butoxide (11 mL, 18 mmol) in THF was placed in a 200 mL round bottom flask purged with nitrogen and fitted with an addition funnel. The solution was cooled to -45 °C and l-isocyanomethanesulfonyl-4-methyl-benzene (1.7 g, 8.8 mmol) in 12 mL anhydrous THF was added dropwise over 10 min. After 10 min, a solution of 2-chloro-6-isobutoxy- benzaldehyde (930 mg, 4.4 mmol) (44-2) in 12 mL THF was added dropwise over 10 min and the reaction mixture was stirred at -45 °C for 2 h. The reaction mixture was then concentrated under vacuum and the resulting residue was taken up in 30 mL water. The resulting aqueous mixture was acidified to pH 6 with 10% aqueous AcOH and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with EtOAc/hexanes to afford 953 mg (97%) 2-(2-chloro-6-isobutoxy-phenyl)acetonitrile (44-4). LCMS (ESI): [M+H]⁺ = 223.9

Step 3. 6-(2-Chloro-6-isobutoxy-phenyl)-2-methylsulfanyl-pyrido[2,3-dJpyrimidin-7-amine (44-5).

[0388] Step 3 was performed as described for Example 1, Step 1 except that the reaction was heated at 60 °C overnight to give 951 mg of 6-(2-chloro-6-isobutoxy-phenyl)-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-amine (44-5). LCMS (ESI): [M+H]+ = 375.0.

Step 4. 7-chloro-6-(2-chloro-6-isobutoxy-phenyl)-2-methylsulfanyl-pyrido[2,3-d] pyrimidine (44-6).

[0389] 6-(2-chloro-6-isobutoxy-phenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-amine (900 mg, 2.4 mmol) (44-5), carbon tetrachloride (48 mL) and tert-butyl nitrite (2.3 mL, 19 mmol) were combined in a 250 mL round bottom flask which was stoppered tightly and heated to 60 °C for 40 min. The reaction mixture was concentrated under vacuum and the crude residue was purified by silica gel chromatography eluting with DCM to afford 420 mg (44%) 7-chloro-6- (2-chloro-6-isobutoxy-phenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (44-6). LCMS (ESI): [M+H]^÷ = 394.0

Steps 5-8. 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-isobutoxy- phenyl)pyrido[2,3-d] pyrimidin-2-amine (1-44).

[0390] Steps 5-8 were performed as described for Example 1, steps 4-7 to give 19 mg of 7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-isobutoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine (1-44). LCMS (ESI): [M+H]+ = 425.1. HPLC retention time (method 1): 1.301 min. Example 48: 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-ylJ-6-[2-chloro-6- (cyclopropylmethoxy)phenyl] pyrido [2,3-dJ pyrimidin-2-amine (1-45)

[0391] 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6- (cyclopropylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-45) was prepared according to the method described for Example 47 using bromomethylcyclopropane in Step 1 and 2- (benzenesulfonyl)-3-phenyl-oxaziridine rather than mCPBA in Step 6. LCMS (ESI): [M+H]⁺ = 423.1. HPLC retention time (method 1): 1.203 min.

Example 49: 7- f ( lR,5S)-6-amino-3-azabicyclo [3.1.0] hexan-3-yl] -6- [2-chloro-6- (tetrahydrofuran-3-ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-46)

H

[0392] 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(tetrahydrofuran- 3-ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-46) was prepared according to the method described for Example 47 using bromomethylcyclopropane in Step 1 and 2- (benzenesulfonyl)-3-phenyl-oxaziridine rather than mCPBA in Step 6. LCMS (ESI): [M+H]⁺ = 423.1. HPLC retention time (method 1): 1.203 min.

Example 50: 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-ylJ-6-(2-chloro-6-methoxy- phenyl)py rido [2,3-d] py rimidin-2-amiiie (1-47)

[0393] 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-methoxy- phenyl)pyrido[2,3-d]pyrimidin-2-amine (1-47) was prepared according to the method described for Example 47 using methyl iodide in step 1. LCMS (ESI): [M+H]⁺= 383.1, HPLC retention time (method 1): 1.016 min.

Example 51: 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-bromo-6-methoxy- phenyl)py rido [2,3-d] py rimidin-2-amine (1-48)

[0394] 7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-bromo-6-methoxy- phenyl)pyrido[2,3-d]pyrimidin-2-amine (1-48) was prepared according to the method described for Example 47 using methyl iodide and 2-bromo-6-hydroxy-benzaldehyde in Step 1 and using the procedure for Step 4 shown herein below. LCMS (ESI): [M+H]⁺= 428.0. HPLC retention time (method 1): 1.043 min. Alternate procedure for Step 4:

[0395] 6-(2-bromo-6-methoxy-phenyl)-7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine: 6-(2-bromo-6-methoxy-phenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-amine (110 mg, 0.29 mmol) was dissolved in 2 mL anhydrous THF and cooled in an ice bath, then 0.5 mL 6 M HC1 and sodium nitrite (80 mg, 1.2 mmol) were added. The reaction was stirred at 0 °C for 15 min, then at room temp for 5 h. During the reaction an additional 2 mL of THF was added to improve solubility. The reaction was filtered and the filtrate was extracted with DCM. The combined extracts were washed with brine, dried over MgS0₄ and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with DCM to afford 29 mg (25%) 6- (2-bromo-6-methoxy-phenyl)-7-chloro-2-methylsulfanyl-pyrido[2,3-d]pyrimidine. LCMS (ESI): [M+H]^÷= 395.9.

Example 52: 7-[(lR,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2,6- dichlorophenyl)py rido [2,3-d] py rimidin-2-amine (1-49)

H

[0396] 7-[(lR,5S, 6r)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2,6-dichlorophenyl) pyrido[2,3-d]pyrimidin-2-amine (1-49) was prepared according to the method described for Example 1 using fc?/t-butyl iV-[(lR,5S, 6r)-3-azabicyclo[3.1.0]hexan-6-yl]carbamate and trimethylamine in DMSO with heating to 100 °C for 2 h in Step 4 and gaseous ammonia in 1,4- dioxane in Step 6. LCMS (ESI): [M+H]⁺= 387.0. HPLC retention time (method 1): 0.920 min. Example 53: 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-ylJ-6-[2-chloro-6- (tetrahydrofuran-2-yImethoxy)phenyl]pyrido[2^-dJpyrimidin-2-amine (1-50) and 7- [(lR,5S,6s)-6-aniino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(tetrahydrofuran-2- ylmethoxy)phenylJpyrido[2,3-d]pyrimidin-2-amine (1-51)

Stepl. l-Allyloxy-3-chloro-2-(chloromethyl)benzene (50-2).

[0397] To (2-allyloxy-6-chloro-phenyl)methanol (5.5 g, 28 mmol) (50-1) in DCM (10 mL) was added thionyl chloride (4 mL, 55 mmol) dropwise over several minutes. After 10 minutes, HPLC analysis showed clean conversion to a single peak. The reaction mixture was diluted with DCM, and the organic layer was washed with water (20 mL), dried over Na₂S0₄, filtered, and concentrated under high vacuum to give 6.0 g of crude l-allyloxy-3-chloro-2- (chloromethyl)benzene (50-2) which was used in the next step without further purification. HPLC retention time (method 2): 1.607 min. Step2. 2-(2-AUyloxy-6-chloro-phenyl)acetonitrile (50-3).

[0398] To l-allyloxy-3-chloro-2-(chloromethyl)benzene (6.0 g, 28 mmol) (50-2) in ethanol (45 mL) was added water (15 mL) followed by sodium cyanide (1.5 g, 30 mmol) and the resulting slurry was heated to 70 °C overnight. The reaction mixture was filtered through celite and then concentrated under vacuum. The resulting slurry was diluted with water (50 mL) and product was extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried with Na₂S04, filtered, and concentrated under high vacuum. The crude oil was purified by flash chromatography eluting with 5-30% EtOAc in hexanes to give 4.4 g (77%) 2-(2-allyloxy-6- chloro-phenyl)acetonitrile (50-3). LCMS (ESI): [M+H]⁺ = 208.1. HPLC retention time (method 2): 1.391 min.

Steps 3-5. teri-Butyl N-[3-[6-(2-chloro-6-hydroxy-phenyl)-2-methylsulfanyl-pyrido[2,3- d] pyrimidin-7-yl] -3-azabicy clo [3.1.0] hexan-6-yl] carbamate (50-6).

[0399] Steps 3-5 were performed as described for Example 47, Steps 3-5 to give 191 mg (21% over 3 steps) of tert-butyl N-[3-[6-(2-chloro-6-hydroxy-phenyl)-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (50-6). LCMS (ESI): [M+Hp = 540.2. HPLC retention time (method 2): 1.368 min.

Step 6. tert-Butyl N-[3-[6-(2-chloro-6-hydroxy-phenyl)-2-methylsulfanyl-pyrido[2,3- d] pyrimidin-7-yl] -3-azabicy clo [3.1.0] hexan-6-yl] carbamate (50-7).

[0400] To a solution of tert- butyl N-[3-[6-(2-allyloxy-6-chloro-phenyl)-2-methylsulfanyl- pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (540 mg, 1.0 mmol) (50- 6) in ethanol (13 mL) and water (2.0 mL) was added tris(triphenylphosphine) rhodium(I) chloride (0.09 mL, 0.10 mmol), followed by triethylenediamine (22 mg, 0.20 mmol) and the resulting mixture was heated to 88 °C for 5 h. The reaction mixture was filtered and then concentrated under vacuum. The resulting residue was purified twice on silica eluting with a gradient of EtOAc in hexanes to give 191 mg (38%) tert-butyl N-[3-[6-(2-chloro-6-hydroxy- phenyl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6- yl]carbamate (50-7). LCMS (ESI): [M+H]^÷= 500.1. HPLC retention time (method 2): 1.184 min. Step 7. tert-buty\ iV-[3-[6-[2-chloro-6-(tetrahydrofuran-2-ylmethoxy)phenyl]-2- methylsulfanyl-pyrido [2,3-d] pyrimidin-7-yl] -3-azabicy clo [3.1.0] hexan-6-yl] carbamate (50- 8).

[0401] To tert-butyl N-[3-[6-(2-chloro-6-hydroxy-phenyl)-2-methylsulfanyl-pyrido[2,3- d]pyrimidin-7-yl]-3-azabicyclo[3.1.0]hexan-6-yl]carbamate (21 mg, 0.041 mmol) (50-7) in DMF (410 μL) was added cesium carbonate (27 mg, 0.082 mmol) followed by 2-(bromomethyl) tetrahydrofuran (9.4 μΐ_^, 0.082 mmol) and the resulting mixture was heated to 100 °C for 2 h. The reaction mixture was quenched with N,N-dimethyl-l,3-propanediamine (10 μΣ,, 0.082 mmol), diluted with EtOAc (5 mL) and water (5 mL), and then acidified with 2 M hydrochloric acid (140 nL, 0.29 mmol). The organic layer was separated, washed with brine (2 x 2 mL), and concentrated under high vacuum to provide 20 mg (83%) tert-butyl N-[3-[6-[2-chloro-6- (tetrahydrofuran-2-ylmethoxy)phenyl]-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-7-yl]-3- azabicyclo[3.1.0]hexan-6-yl]carbamate (50-8) which was used in the next reaction without further purification. LCMS (ESI): [M+H]^÷= 548.1. HPLC retention time (method 2): 1.297 and 1.309 min as a pair of rotamers.

Steps 8-10. 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6- (tetrahydrofuran-2-ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-50) and 7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(tetrahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-ainine (1-51).

[0402] Steps 8-10 were performed as described for Example 47, Steps 6-8 to provide a mixture of rotamers which were separated by reverse phase HPLC (1" Phenomenex Luna column, 0.1% TFA in water/ACN) to give 10 mg (31% over 3 steps) of 7-[(lR,5S,6s)-6-amino- 3 -azabicy clo[3.1.0] hexan-3 -y 1] -6- [2-chloro-6-(tetrahydrofuran-2-ylmethoxy)phenyl] pyrido [2,3 - d]pyrimidin-2-amine (1-50) and 10 mg (31% over 3 steps) of 7-[(lR,5S,6s)-6-amino-3- azabicyclo[3.1.0]hexan-3-yl)-6-[2-chloro-6-(tetrahydrofuran-2-ylmethoxy)phenyl]pyrido[2,3- d]pyrimidin-2-amine (1-51). 1-50: LCMS (ESI): [M+H]⁺= 453.2. HPLC retention time (method 2): 0.617 min. 1-51: LCMS (ESI): [M+H]⁺= 453.2, HPLC retention time (method 2): 0.719 min. Example 54: 2- [2- [2-amino-7- [(lR,5S)-6-amino-3-azabicyclo [3.1.0] hexaii-3-yl] pyrido[2,3- d]pyrimidin-6-yl]-3-chloro-phenoxy] acetic acid (1-52)

H

[0403] 2-[2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3- d]pyrimidin-6-yl]-3-chloro-phenoxy]acetic acid (1-52) was prepared according to the method described for Example 53 using tenf-butyl bromoacetate in Step 7. LCMS (ESI): [M+H]⁺ = 427.0. HPLC retention time (method 1): 0.920 min.

Example 55: 4-[2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3- d]pyrimidin-6-yl]-3-chloiO-phenoxy]butanoic acid (1-53)

o

H

[0404] 4-[2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3- d]pyrimidin-6-yl]-3-chloro-phenoxy]butanoic acid (1-53) was prepared according to the method described for Example 53 using tert-butyl 3-bromopropanoate in Step 7. LCMS (ESI): [M+H]⁺ = 455.1 . HPLC retention time (method 1): 0.993 min. Example 56: 7-[(3R)-3-(aminomethyl)pyrrolidin-l-yl]-6-(2-chIoro-6-isobutoxy- phenyl)py rido [2,3-d] py rimidin-2-amiiie (1-54)

[0405] 7-[(3R)-3-(aminomethyl)pyrrolidin-l-yl]-6-(2-chloro-6-isobutoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine (1-54) was prepared according to the method described for Example 47 using (S)-3-(iV-Boc-aminomethyl)pyrrolidine while heating to 90 °C overnight in Step 5 and gaseous ammonia in 1,4-dioxane in Step 7. LCMS (ESI): [M+H]⁺ = 427.2, HPLC retention time (method 2): 0.942 min.

Example 57: 7-[(3S)-3-(aminomethyl)pyrrolidin-l-yl]-6-(2-chloro-6-isobutoxy- phenyl)py rido [2,3-d] py rimidin-2-amine (1-55)

[0406] 7-[(3S)-3-(aminomethyl)pyrrolidin-l-yl]-6-(2-chloro-6-isobutoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine (1-55) was prepared according to the method described for Example 47 using (R)-3-(N-Boc-aminomethyl)pyrrolidine while heating to 90 °C overnight in Step 5 and gaseous ammonia in 1,4-dioxane in Step 7. LCMS (ESI): [M+H]⁺ = 427.2. HPLC retention time (method 1): 1.316 min. Examples 58: 7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-6-[2-

(trifluoromethyl)pheiiyl]pyrido[2,3-d]pyrimidiii-2-amine (1-56) and 7-(4-methylpiperazin- l-yl)-6- [2-(trifluoromethyl)phenyl] pyrido [2,3-dJ pyrimidin-2- amine (1-57)

Step 1. 6-bromo-7-(4-methylpiperazin-l-yI)-2-methyIsulfanyl-pyrido[2,3-d]pyrimidine (56- 1).

[0407] Step 1 was performed as described for Example 33, Step 2 from JV-methylpiperazine to give 1.0 g of 6-bromo-7-(4-methylpiperazin-l-yl)-2-methylsulfanyl-pyrido[2,3-d]pyrimidine (56-1). LCMS (ESI): [M+H]⁺ = 354.0.

Step 2. 7-(4-methylpiperazin-l-yl)-2-methylsulfanyl-6-[2-(trifluoromethyl)

phenyl] pyrido [2,3-d] pyrimidine (56-2).

[0408] Step 2 was performed as described for Example 33, Step 3 to give 200 mg of 7-(4- memylpiperazin-l-yl)-2-methylsulfanyl-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimi (56-2). LCMS (ESI): [M+H]⁺ = 420.0.

Step 3. 7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-2-methylsulfinyl-6-[2-(trifluoromethyl) phenyl] pyrido[2,3-d] pyrimidine (56-3).

[0409] Step 3 was performed as described for Example 33, Step 4 using two equivalents of 2-(benzenesulfonyl)-3-phenyl-oxaziridine to give 7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-2- memylsulfmyl-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidine (56-3) as a crude residue that was used in the next step without purification. LCMS (ESI): [M+H]⁺ = 452.1. Step 4. 7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3- dJpyrimidin-2-amine (1-56).

[0410] Step 4 was performed as described in Example 33, Step 5 to give 69 mg (46%) of 7- (4-memyl-4-oxido-piperazin-4-ium-l-yl)-6-[2-(trifluoromemyl)phenyl]pyrido[2,3-d]pyrimidin- 2-amine (1-56). LCMS (ESI): [M+H]^÷= 404.4. HPLC retention time (method 1): 1.080 min.

Step 5. 7-(4-methylpiperazin- l-yl)-6- [2-(trifluoromethyl)phenyl] pyrido [2,3-d] pyrimidiii-2- amine (1-57).

[0411] 7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine (30 mg, 0.070 mmol) (1-56), sodium sulfate (110 mg) and carbon disulfide (130 μΣ,, 2.2 mmol) were combined in 0.8 niL DMF and the resulting mixture was stirred at room temp overnight. The reaction mixture was filtered and purified by reverse phase HPLC (1" Phenomenex Luna column, 0.1% TFA in water/ ACN) to give 4.0 mg (11%) of 7-(4- methylpiperazin- 1 -yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine (1-57). LCMS (ESI): [M+H]^÷= 388.4. HPLC retention time (method 1): 1.019 min.

Example 58: 6-(2-ethoxypheiiyl)-7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)pyrido[2,3- d]pyrimidin-2-amine (1-58)

Ό

[0412] 6-(2-ethoxyphenyl)-7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)pyrido[2,3- d]pyrimidin-2-amine (1-58) was prepared according to the method used to prepare 1-56 using 2- ethoxyphenylboronic acid in Step 2. LCMS (ESI): [M+Hp= 381.1, HPLC retention time (method 1): 1.086 min. Example 59: 6-(2-ethoxyphenyl)-7-(4-methylpiperazin-l-yl)pyrido[2,3-d]pyrimidin-2- aniine (1-59)

[0413] 6-(2-ethoxyphenyl)-7-(4-methylpiperazin- 1 -yl)pyrido[2,3-d]pyrimidin-2-amine (I was prepared according to the method used to prepare 1-57. LCMS (ESI): [M+H]⁺= 365.1. HPLC retention time (method 1): 1.028 min.

Example 60: 6-(2-chloro-6-isobutoxy-phenyl)-7-[3-(5-fluoro-2-methyl-anilino)pyrrolidin-l- yl]pyrido[2,3-d]pyrimidin-2-amine (1-60)

[0414] 6-(2-chloro-6-isobutoxy-phenyl)-7-[3-(5-fluoro-2-methyl-anilino)pyrrolidin- 1 - yl]pyrido[2,3-d]pyrimidin-2-amine (1-60) was prepared according to the methods described in Example 47, using the N-(5-fluoro-2-methyl-phenyl)pyrrolidin-3-amine (60-4) in Step 5. LCMS (ESI): [M+fff = 521.3. HPLC retention time (method 3): 1.510 min.

60-1 60-2 60-3 60-4 Preparation of N-(5-fluoro-2-methyI-phenyl)pyrrolidin-3-amine (60-4)

Step 1. ferf-butyl 3-(5-fluoro-2-methyl-anUino)pyrrolidine-l-carboxylate (60-3).

[0415] To l-N-Boc-3-pyrrolidinone (700 mg, 3.8 mmol), 5-fluoro-2-methyl-aniline (94 mg, 0.75 mmol) and acetic acid (0.020 mL, 0.38 mmol) in methanol (4.0 mL) at 0 °C was added sodium cyanoborohydride (94 mg, 1.5 mmol) portion- wise. The ice bath was removed and the reaction mixture was stirred at room temperature for 4 h. The resulting mixture was

concentrated under a stream of nitrogen to afford a yellow oil. The oil was purified by silica gel chromatography eluting with ethyl acetate/hexanes to afford tert-butyl 3-(5-fluoro-2-methyl- anilino)pyrrolidine-l-carboxylate 60-3 (276 mg) as a crude residue that was carried forward without further purification.

Step 2. N-(5-fluoro-2-methyl-phenyl)pyrrolidin-3-amine TFA salt (60-4).

[0416] To tert-butyl 3-(5-fluoro-2-methyl-anilino)pyrrolidine-l-carboxylate (60-3) (280 mg, 0.94 mmol) in DCM (2 mL) was added trifluoroacetic acid (1.0 mL, 0.94 mmol) and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated under a stream of nitrogen to give the TFA salt of N-(5-fluoro-2-methyl- phenyl)pyrrolidin-3 -amine 60-4 (340 mg) as a crude residue that was used in the next step without further purification.

Example 61: Antimicrobial Activity in various Bacterial Strains.

[0417] Minimum Inhibitory Concentrations (MICs) are determined by the broth

microdilution method in accordance with the Clinical and Laboratory Standards Institute (CLSI) guidelines. In brief, organism suspensions are adjusted to a 0.5 McFarland standard to yield a final inoculum between 3 x 10^s and 7 x 10^s colony-forming units (CFU)/mL. Drug dilutions and inocula are made in sterile, cation adjusted Mueller-Hinton Broth (Beckton Dickinson). An inoculum volume of 100 uL is added to wells containing 100 |jL of broth with 2-fold serial dilutions of drug. Inoculated microdilution trays are incubated in ambient air at 35° C for 18-24 hr. Following incubation, the lowest concentration of the drug that prevents visible growth (OD600 nm < 0.05) is recorded as the MIC. Performance of the assay is monitored by the use of laboratory quality-control strains and levofloxacin, a compound with a defined MIC spectrum, in accordance with CLSI guidelines. Typically, compounds of the present invention have MIC values of 0.25 - 32 ng/mL. These data are presented in Table 1. The compounds were run against Escherichia coli KD65 (E. coli), Klebsiella pneumoniae ATCC 43816 (K. pneum), and Staphylococcus aureus ATCC 29213 (S. aureus).

[0418] Table 1: MIC data of compounds of the disclosure against Escherichia Coli KD65 (E. Coli), Klebsiella pneumoniae ATCC ' 43816 (K. Pneum), and Staphylococcus aureus ATCC 29213 (S. aureus). +++ indicates an MIC of less than 16 mg/L, ++ indicates an MIC between about 16 mg/Land about 64 mg/L, and + indicates an MIC greater than about 64 mg/L. ND indicates the value was not determined.

TABLE 1: MIC activity

Equivalents

[0419] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

Claims

CLAIMS What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof,

wherein:

R1 is (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5, aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R6;

R₂ is H, (C1-C4) alkyl, (C1-C4) haloalkyl, halogen, -OR5', aryl, or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more R7;

R3 is (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, -OH, -NH₂, (C1-C4) alkylamino, or (C1-C4) dialkylamino;

or R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form an aryl ring; or R1 and R3 when on adjacent atoms together with the carbon atoms to which they are attached form a heteroaryl ring;

R4 is a heterocycloalkyl ring;

R5 is (C1-C6) alkyl, -(CH₂)_m(C3-C7) cycloalkyl, or -(CH₂)mheterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and

-C(0)0(C1-C4) alkyl; R5' is (C1-C6) alkyl, -(CH_)o(C3-C7) cycloalkyl, or -(CH₂)₀heterocycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R6 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, halogen, -NH₂, (C1-C4) alkylamino, (C1-C4) dialkylamino, or

-N(H)S(0)q (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R7 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, halogen, -NH₂, (C1-C4) alkylamino, (C1-C4) dialkylamino, or

-N(H)S(0)_Q (C1-C4) alkyl, wherein the (C1-C4) alkyl is optionally substituted with one or more substituents selected from -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

each R8 is independently (C1-C4) alkyl, (Ct-C4) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, halogen, -OH, -CN, -NR10R11, -C(0)NH₂, or oxide, wherein the

(C1-C4) alkyl is optionally substituted with one or more substituents selected from -NR12R13, -C(0)OH, -OH, and -C(0)0(C1-C4) alkyl;

or two R8 on adjacent atoms together form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9; or two R8 on adjacent atoms together form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9; or two R8 on the same carbon atom together form a (C3-C7) spirocycloalkyl ring, wherein the spirocycloalkyl ring is optionally substituted with one or more R9; or two R8 on the same carbon atom together form a spiroheterocycloalkyl ring, wherein the

spiroheterocycloalkyl ring is optionally substituted with one or more R9;

each R9 is independently (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy,

(C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, -OH, halogen, -CN, -NH₂, (C1-C4) alkylamino, or (C1-C4) dialkylamino;

each R1o and R11 is independently H, (C1-C4) alkyl, (C3-C6) cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the (C3-C6) cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from (C1-C4) alkyl,

(C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, CN, -NH2, and -OH; or RJO and R11 together with the nitrogen atom to which they are attached form a heterocycloalkyl ring optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, (C1-C4) hydroxyalkyl, -OH, halogen, -NH₂, (C1-C4) alkylamino, and (C1-C4) dialkylamino;

each R]₂ and R13 is independently H, (C1-C4) alkyl, or (C3-C7) cycloalkyl, wherein the alkyl is optionally substituted with one or more substituents selected from CN, -Nth, -OH, and halogen;

q is 1 or 2; and

each m, n, o, and p is independently 0, 1, 2, or 3.

2. The compound of claim 1, wherein R₂ is H or halogen.

3. The compound of claim 1 or 2, wherein R1 is (C1-C4) haloalkyl, halogen, -OR5, or heteroaryl optionally substituted with one or more R6.

4. The compound of any one of claim 1 or 2, wherein R1 and R3 together with the carbon atoms to which they are attached form an aryl ring.

5. The compound of any one of claims 1 to 4, wherein R₄ is azetidinyl, pyrrolidinyl, piperidinyl, or piperazinyl.

6. The compound of any one of claims 1 to 5, wherein two R8 when on adjacent atoms form a (C3-C7) cycloalkyl ring, wherein the cycloalkyl ring is optionally substituted with one or more R9.

7. The compound of any one of claims 1 to 5, wherein two R8 when on adjacent atoms form a heterocycloalkyl ring, wherein the heterocycloalkyl ring is optionally substituted with one or more R9.

8. The compound of any one of claims 1 to 5, wherein two R8 when on the same carbon atom form a spiroheterocycloalkyl ring, wherein the spiroheterocycloalkyl ring is optionally substituted with one or more R9.

9. The compound of any one of claims 1 to 8, wherein Rs is -NH₂.

10. The compound of any one of claims 1 to 5, wherein R8 is halogen, -OH, -NR1oR11, -C(0)NH₂, oxide, or (C1-C4) alkyl optionally substituted with one or more substituents selected from -NR₁₂R₁₃ and OH.

11. The compound of claim 1, having Formula (la):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

12. The compound of claim 1, having Formula (lb):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The compound of claim 1, having Formula (Ic)

( ) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

14. The compound of claim 1, having Formula (Id-X):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

15. The compound of claim 1 , having Formula (Ie-X) or Formula (If-X):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The compound of claim 1, having Formula (Ig):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The compound of claim 1, having Formula (Ih):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The compound of claim 1, having Formula (Ii-X):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

The compound of claim 1, having Formula (Ij-X):

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

20. The compound of claim 1, selected from the group consisting of:

7-[( lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2 -amine;

7-(4-amino-l-piperidyl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,8-diazaspiro[4.5]decan-8-yl)-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[4-(aminomethyl)-l-piperidyl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[3-(aminomethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

[l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3-yl]methanol;

l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidine-3-carboxamide; l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-3-(aminomethyl)pyrrolidin-3-ol;

7- [3 -(aminomethy l)-3 -fluoro-pyrrolidin- 1 -y 1] -6-(2, 6-dichlorophenyl)pyrido[2, 3-d] pyrimidin-2- amine;

7-[3-(l-aminoethyl)pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine; 6-(2,6-dichlorophenyl)-7-[4-(methylaminomethyl)-l-piperidyl]pyrido[2,3-d]pyrimidin-2-amine; 7-[3-(l-aminoethyl)azetidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-2-amine;

7- [4-( 1 -aminoethy 1)- 1 -piperidyl] -6-(2,6-dichlorophenyl)pyrido[2, 3-d] pyrimidin-2-amine;

7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-b]pyrrol-5-yl)-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine;

3 - [ [ 1 - [2-amino-6-(2,6-dichlorophenyl)py rido[2, 3-d] pyrimidin-7-yl]pyrrolidin-3 - yl]methylamino]propanenitrile;

2-(((l-(2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl)pyrrolidin-3- yl)methyl)amino)ethan- 1 -ol;

7-[3-[(cyclopropylamino)methyl]pyrrolidin-l-yl]-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidi 2-amine;

6- (2,6-dichlorophenyl)-7-[3-[(2,2-difluoroethylamino)methyl]pyrrolidin-l-yl]pyrido[2,3- d]pyrimidin-2-amine;

[3-amino-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]pyrrolidin-3- yl]methanol;

[(3R,4R)-l-[2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-yl]-4- (hydroxymethyl)pyrrolidin-3-yl]methanol;

7- (3 -aminopyrrolidin- 1 -yl)-6-( 1 -naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(3-aminoazetidin-l-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3J^]hexan-3-yl)-6-(l-mphthyl)pyrido[2,3-d]pyrimidm-2- amine;

7-(2,8-diazaspiro[4J]decan-8-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,7-diazaspiro[3.5]nomn-7-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

7-(2,3,3a,4,6,6a-hexahydro-lH-pyrrolo[3,4-c]pyrrol-5-yl)-6-(l-naphthyl)pyrido[2,3-d]pyrimid 2-amine;

7-[3-(aminomethyl)azetidin-l -yl]-6-(l -naphthyl)pyrido[2,3-d]pyrimidin-2-amine;

6-(l -naphthyl)-7-piperazin-l-yl-pyrido[2,3-d]pyrimidin- 2-amine; 7-(3-aminoazetidin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-ami

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(5-fluoro-6-methoxy-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methyl-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

2-[4-[2-[2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl)pyrido[2,3-d]pyrimidin-

6- yl]-3-chloro-phenyl]pyrazol- 1 -yl]acetic acid;

7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methoxy-4- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(2-methylthiazol-5- yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-(6-ethoxy-3 - pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6- [6-(dimethy lamino)-3 - pyridyl]phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(4-pyridyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(6-methyl-3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-( 1 -methylpyrazol-4- yl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7- [( 1 R, 5 S)-6-amino-3 -azabicyclo [3.1.0] hexan-3 -yl] -6- [2-chloro-6-(6-methoxy-3 - pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

N-[5-[2-[2-amino-7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-

6- yl]-3-chloro-phenyl]-2-pyridyl]methanesulfonamide;

7- [(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(3- pyridyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine; 7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-isobutoxy- phenyl)pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6- (cyclopropylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(tetrahydrofuran-3- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-chloro-6-methoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2-bromo-6-methoxy-phenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6r)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-(2,6-dichlorophenyl)pyrido[2,3- d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]-6-[2-chloro-6-(te1rahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

7-[(lR,5S,6s)-6-amino-3-azabicyclo[3 .0]hexan-3-yl]-6-[2-chloro-6-(te1rahydrofuran-2- ylmethoxy)phenyl]pyrido[2,3-d]pyrimidin-2-amine;

2- [2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-6-yl^

3- chloro-phenoxy]acetic acid;

4- [2-[2-amino-7-[(lR,5S)-6-amino-3-azabicyclo[3.1.0]hexan-3-yl]pyrido[2,3-d]pyrimidin-6-yl^ 3-chloro-phenoxy]butanoic acid;

7- [(3R)-3 -(aminomethy l)pyrrolidin- 1 -yl] -6-(2-chloro-6-isobutoxy-phenyl)pyrido[2, 3 - d]pyrimidin-2-amine;

7- [(3 S)-3 -(aminomethyl)pyrrolidin- 1 -yl] -6-(2-chloro-6-isobutoxy-phenyl)pyrido [2,3 - d]pyrimidin-2-amine;

7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3- d]pyrimidin-2-amine;

7-(4-methylpiperazin-l-yl)-6-[2-(trifluoromethyl)phenyl]pyrido[2,3-d]pyrimidin-2-amine; 6-(2-et oxyphenyl)-7-(4-methyl-4-oxido-piperazin-4-ium-l-yl)pyrido[2,3-d]pyrimidin-2-

6-(2-ethoxypheny l)-7-(4-methy lpiperazin- 1 -yl)pyrido[2,3 -d]pyrimidin-2-amine; and

6-(2-chloro-6-isobutoxy-phenyl)-7-[3-(5-fluoro-2-methyl-anilino)pyrrolidin-l-yl]pyrido[2,3- d]pyrimidin-2-amine;

or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

21. A pharmaceutical composition comprising a compound of any one of claims 1 to 20 and a pharmaceutically acceptable carrier.

22. A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 20.

23. The method according to claim 22, wherein said bacterial infection is a gram-negative bacterial infection.

24. The method according to claim 23, wherein said gram-negative bacterial infection is Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacleriaceae, Haemophilus, Franciscellaceae or a Neisseria species.

25. The method according to claim 22, wherein said bacterial infection is a gram-positive bacterial infection.

26. The method according to claim 25, wherein said gram-positive is Staphylococcus, Streptococcus, Enterococcus, Mycobacterium, Bacillus, Clostridium or a Listeria species.

27. A method for treating a bacterial infection in a subject comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 21.

28. The method according to claim 27, wherein said bacterial infection is a gram-negative bacterial infection.

29. The method according to claim 28, wherein said gram-negative bacterial infection is Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Alcaligenes xylosoxidans, Enterobacteriaceae, Haemophilus, Acinetobacter, Franciscellaceae or a Neisseria species.

30. The method according to claim 27, wherein said bacterial infection is a gram-positive bacterial infection.

31. The method according to claim 30, wherein said gram-positive bacterial infection is Staphylococcus, Streptococcus, Enterococcus, Bacillus, Clostridium, or a Listeria species.