Thyroxine receptor beta agonist compounds

文档序号：554784 发布日期：2021-05-14 浏览：38次中文

阅读说明：本技术 甲状腺素受体β促效剂化合物 (Thyroxine receptor beta agonist compounds ) 是由 T·A·基尔施伯格 R·哈尔康卜徐英姿 F·A·罗曼罗于 2019-08-23 设计创作，主要内容包括：本文提供化合物,优选甲状腺素受体βTHRβ激动剂化合物、其组合物,及其制备方法,及激动THRβ的方法,及用于治疗THRβ介导的病症的方法。(Provided herein are compounds, preferably thyroxine receptor beta THR beta agonist compounds, compositions thereof, and methods of making the same, as well as methods of agonizing THR beta, and methods for treating THR beta mediated disorders.)

1. A compound of the formula (I),

or a pharmaceutically acceptable salt thereof, wherein:

ring a together with the carbonyl (keto) group within the ring forms a 5-membered heterocyclic ring containing 1 to 3 ring heteroatoms selected from the group consisting of N, O and S, wherein the heterocyclic ring is optionally through 1 to 2C₁-C₃Alkyl or C₃-C₄Cycloalkyl substituted, and wherein the carbonyl (keto) group is not adjacent to an atom bound to X;

R¹is C optionally substituted by 1 to 5 halogen or hydroxy₁-C₄Alkyl radical, C₃-C₅Cycloalkyl, CON (R)¹⁰)₂Or NR¹⁰COR¹⁰；

R²Is H or C₁-C₃An alkyl group;

l is O, CH₂、S、SO、SO₂、CO、CHF、CF₂、C(R¹¹)CN、CHR¹¹Or C (R)¹¹)R¹¹；

R³And R⁴Independently Cl, Br, methyl or ethyl;

R⁵is H, halo, C₁-C₄Alkyl or C₃-C₄A cycloalkyl group;

or R⁵And R⁴And the intervening atoms together form a 5-to 7-membered cycloalkyl group or a 5-to 7-membered heterocyclic ring containing 1 to 2 ring heteroatoms;

x is absent, O, NR¹²、C(O)NR¹²、NR¹²C(O)、CR¹²R¹²、OCR¹²R¹²、CR¹²R¹²O、NR¹²CR¹²R¹²、CR¹²R¹²NR¹²、SO₂NR¹²Or NR¹²SO₂；

Each R¹⁰Independently is C₁-C₃Alkyl or H;

each R¹¹Independently is C optionally substituted with 1 to 5 halo₁-C₂Alkyl, or two R¹¹The groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring; and

each R¹²Independently H or methyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having formula (IIA) or (IIB):

wherein R is¹、R²、R³、R⁴、R⁵X and L are as defined in claim 1.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having formula (VD):

wherein R is¹、R²、R³、R⁴And R⁵Is as defined in claim 1.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein:

R¹is optionally substituted by 1 to 2 halogen or hydroxy groupsC of (A)₁-C₄Alkyl, or C₃-C₅A cycloalkyl group.

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein:

R¹is isopropyl, tert-butyl, HO-CH (CH)₃)-、HO-CH(CH₂CH₃)-、HO-C(CH₃)₂-、HO-CH₂CH(CH₃) -, cyclopropyl or

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein:

R²is H or-CH₃。

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein:

R³is chlorine or-CH₃。

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein:

R⁴is chlorine or-CH₃；

Or R⁵And R⁴And the intervening atoms together form a 5-to 6-membered cycloalkyl group.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein:

R⁵and R⁴And the intervening atoms together form a cyclopentyl group.

10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein:

R⁵Is H or fluorine.

11. The compound of any one of claims 1, 2, and 4-10, or a pharmaceutically acceptable salt thereof,

wherein:

x is a bond.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein:

x is NR¹²C(O)、OCR¹²R¹²Or NR¹²CR¹²R¹²(ii) a And

each R¹²Independently H or methyl.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein:

x is-OCH₂-、-NHCH₂-、-NHC(O)-、-N(CH₃)CH₂-or-N (H) CH (CH)₃)-。

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein:

l is O, CH₂、SO₂、CO、CHR¹¹Or C (R)¹¹)R¹¹(ii) a And

each R¹¹Independently methyl or ethyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein:

l is O, CH₂、SO₂Or CO.

16. A compound of the formula (I-a),

or a tautomer or an N-oxide thereof, or an isotopic isomer of each thereof, or a prodrug of each of the foregoing, or a stereoisomer of the foregoing, or a pharmaceutically acceptable salt of each of the foregoing, or a solvate of each of the foregoing, wherein:

ring a together with the carbonyl (keto) group within the ring forms a 5-membered heterocyclic ring containing 1 to 3 ring heteroatoms selected from the group consisting of N, O and S, wherein the heterocyclic ring is optionally through 1 to 2C ₁-C₃Alkyl or C₃-C₄Cycloalkyl substituted, and wherein the carbonyl (keto) group is not adjacent to an atom bound to X;

R¹is C₁-C₄An alkyl group; c optionally substituted by 1 to 5 halo₁-C₄An alkyl group; c₃-C₅Cycloalkyl, CON (R)¹⁰)₂Or NR¹⁰COR¹⁰Wherein each R¹⁰Independently is C₁-C₃Alkyl or H;

R²is H or C₁-C₃An alkyl group;

l is O, CH₂、S、SO、SO₂、CO、CHF、CF₂、C(R¹¹)CN、CHR¹¹Or C (R)¹¹)R¹¹Wherein each R¹¹Is C optionally substituted by 1 to 5 halo₁-C₂Alkyl, or 2R¹¹The groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring;

each R³And R⁴Independently Cl, Br, methyl or ethyl;

R⁵is H, halo, C₁-C₄Alkyl or C₃-C₄Cycloalkyl, or R⁵And R⁴And the intervening atoms together form a 5-to 7-membered cycloalkyl group or a 5-to 7-membered heterocyclic ring containing 1 to 2 ring heteroatoms;

x is absent, or is O, NR¹²、C(O)NR¹²、NR¹²C(O)、CR¹²R¹²、OCR¹²R¹²、CR¹²R¹²O、NR¹²CR¹²R¹²、CR¹²R¹²NR¹²、SO₂NR¹²Or NR¹²SO₂Wherein each R¹²Independently H or methyl.

17. A compound selected from the compounds in table 1, or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

19. A method of agonizing the thyroxine receptor β THR β comprising contacting an effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 18, with the THR β.

20. A method of treating a disorder mediated by THR β in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, or a therapeutically effective amount of a pharmaceutical composition of claim 18.

21. The method of claim 20, wherein the disorder is nonalcoholic steatohepatitis (NASH).

Technical Field

The present invention relates to compounds, preferably thyroxine receptor beta (THR β) agonist compounds, compositions thereof, and methods of making the same, as well as methods of promoting THR β and methods for treating conditions mediated by THR β.

Background

Advantageous effects resulting from treatment of hyperthyroidism or hypothyroidism patients with endogenous ligands of T3/T4 or early analogues of these endogenous ligands have been described in the reference (Richardson Hill jr., S., et al, J.Clin. invest.)1960,39, 523-533. These early studies and similar follow-up studies established that the heart is the major organ for the manifestation of side effects of both hyperthyroidism and hypothyroidism (Klein, I.) et al, Circulation, 2007, 1725-1735). Specifically, tachycardia, cardiac hypertrophy (hyperthyroidm), arrhythmia, and atrial fibrillation are serious problems. In addition, it has also been noted that increased bone turnover results in decreased bone mineral density. The negative effects at both cardiac and bone sites have been linked to the pro-effects of THR α isoforms, while the beneficial effects of THR pro-effects in the liver have been largely linked to THR β isoforms (Sinha (R.A.), et al, natural reviews: endocrinology 2018,14, 259-269).

Diseases or disorders associated with THR β include nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, and hypercholesterolemia. There is a need for thyroxine analogues, such as those that are agonists of THR β, and preferably those that avoid the undesirable effects of hyperthyroidism and hypothyroidism, and maintain the beneficial effects of thyroxine, for example, for treating patients with nonalcoholic steatohepatitis (NASH). In particular, there is a need to develop novel thyroxine analogues that are selective agonists of THR β, and preferably those that avoid the undesirable effects associated with the agonistic effects of THR α, and maintain the beneficial effects of thyroxine, e.g., for treating patients with nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver (NAFLD), metabolic syndrome, dyslipidemia, hypertriglyceridemia, or hypercholesterolemia.

Disclosure of Invention

In one aspect, provided herein is a compound of formula (I):

Wherein:

R¹is C optionally substituted by 1 to 5 halogen or hydroxy₁-C₄Alkyl radical, C₃-C₅Cycloalkyl, CON (R)¹⁰)₂Or NR¹⁰COR¹⁰；

R²Is H or C₁-C₃An alkyl group;

l is O, CH₂、S、SO、SO₂、CO、CHF、CF₂、C(R¹¹)CN、CHR¹¹Or C (R)¹¹)R¹¹；

R³And R⁴Independently Cl, Br, methyl or ethyl;

R⁵is H, halo, C₁-C₄Alkyl or C₃-C₄A cycloalkyl group;

or R⁵And R⁴And the intervening atoms together form a 5-to 7-membered cycloalkyl group or a 5-to 7-membered heterocyclic ring containing 1 to 2 ring heteroatoms;

x is absent, O, NR¹²、C(O)NR¹²、NR¹²C(O)、CR¹²R¹²、OCR¹²R¹²、CR¹²R¹²O、NR¹²CR¹²R¹²、CR¹²R¹²NR¹²、SO₂NR¹²Or NR¹²SO₂；

Each R¹⁰Independently is C₁-C₃Alkyl or H;

each R¹¹Independently is C optionally substituted with 1 to 5 halo₁-C₂An alkyl group, a carboxyl group,

or two R¹¹The groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring; and

each R¹²Independently H or methyl.

In some embodiments, the compound is a compound of formula (IIA) or (IIB):

wherein R is¹、R²、R³、R⁴、R⁵X and L are as defined for the compounds of formula (I).

In some embodiments, the compound is a compound of formula (VD):

wherein R is¹、R²、R³、R⁴And R⁵As defined according to claim 1.

In some embodiments, R¹Is C optionally substituted by 1 to 2 halogen or hydroxy₁-C₄Alkyl radicalOr C₃-C₅A cycloalkyl group. In some embodiments, R¹Is isopropyl, tert-butyl, HO-CH (CH)₃)-、HO-CH(CH₂CH₃)-、HO-C(CH₃)₂-、HO-CH₂CH(CH₃) -, cyclopropyl or

In some embodiments, R²Is H or-CH₃。

In some embodiments, R³Is chlorine or-CH₃。

In some embodiments, R⁴Is chlorine or-CH₃(ii) a Or R⁵And R⁴And the intervening atoms together form a 5-to 6-membered cycloalkyl group. In some embodiments, R⁵And R⁴And the intervening atoms together form a cyclopentyl group. In some embodiments, R⁵Is H or fluorine.

In some embodiments, X is a bond. In some embodiments, X is NR¹²C(O)、OCR¹²R¹²Or NR¹²CR¹²R¹²(ii) a And each R¹²Independently H or methyl. In some embodiments, X is-OCH₂-、-NHCH₂-、-NHC(O)-、-N(CH₃)CH₂-or-N (H) CH (CH)₃)-。

In some embodiments, L is O, CH₂、SO₂、CO、CHR¹¹Or C (R)¹¹)R¹¹(ii) a And each R¹¹Independently methyl or ethyl. In some embodiments, L is O, CH₂、SO₂Or CO.

In some embodiments, provided herein is a compound selected from the compounds in table 1, or a pharmaceutically acceptable salt thereof.

In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein and at least one pharmaceutically acceptable excipient.

In one aspect, provided herein is a method of promoting thyroxin receptor beta (THR β), comprising contacting an effective amount of a compound provided herein or an effective amount of a pharmaceutical composition provided herein with said THR β.

In one aspect, provided herein is a method of treating a condition mediated by THR β in a patient, comprising administering to the patient a therapeutically effective amount of a compound provided herein, or a therapeutically effective amount of a composition provided herein. In some embodiments, the disorder is non-alcoholic steatohepatitis (NASH).

Detailed Description

Definition of

As used herein, the following definitions shall apply unless otherwise indicated herein. In addition, any term or symbol used herein shall have its ordinary meaning in the art if it is not defined as set forth below.

"comprising" is intended to mean that the compositions and methods include the elements recited herein, but not excluding other elements. When "consisting essentially of … …" is used to define compositions and methods, it is intended to exclude other elements having any significance to the combination. For example, a composition consisting essentially of the elements as defined herein should not exclude other elements that do not materially affect the basic and novel characteristics of the invention as claimed herein. "consisting of … …" shall mean excluding, for example, more than trace amounts of other ingredients and substantial method steps recited herein. Embodiments defined by each of these transition terms are within the scope of the invention.

An "effective amount" or dose of a compound or composition refers to that amount of the compound or composition that optionally results in the desired result, based on the disclosure herein. An effective amount can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example (but not limited to) by determining LD₅₀(dose lethal to 50% of the population) and ED₅₀(a therapeutically effective dose in 50% of the population).

The term "excipient" as used herein means an inert or inactive substance that can be used to produce a drug or pharmaceutical product (e.g., a lozenge containing a compound of the present invention as an active ingredient). The term excipient may include a variety of substances including, but not limited to, any substance that acts as a binder, disintegrant, coating, compression/encapsulation aid, cream or emulsion, lubricant, solution for parenteral administration, material for chewable tablets, sweetener or flavoring agent, suspending/gelling agent, or wet granulation agent. Binders include, for example, carbomer, polyvinylpyrrolidone, xanthan gum, and the like; coatings include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, and the like; compression/encapsulation aids include, for example, calcium carbonate, glucose, fructose dc (dc ═ directly compressible), honey dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose, and the like; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, and the like; creams or lotions include, for example, maltodextrin, carrageenan, and the like; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, and the like; materials for chewable lozenges include, for example, glucose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), and the like; suspending/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, and the like; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, and the like; and wet granulation agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, and the like.

"patient" refers to a mammal and includes both human and non-human mammals. Examples of patients include, but are not limited to, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, goats, sheep, cows, and humans. In some embodiments, the patient is a human.

"pharmaceutically acceptable" means safe and non-toxic, preferably for in vivo, more preferably, for human administration.

"pharmaceutically acceptable salt" refers to a salt, which is pharmaceutically acceptable. The compounds described herein may be administered as pharmaceutically acceptable salts.

"prodrug" refers to a compound that, upon administration, is metabolized or otherwise converted to a compound (or drug) that is biologically active or more active with respect to at least one property. Prodrugs are chemically modified in a manner that renders the prodrug less or inactive relative to the drug, but such chemical modification results in the production of the corresponding drug by metabolic or other biological processes upon administration of the prodrug. Prodrugs can have altered metabolic stability or transport properties, fewer side effects or lower toxicity, or improved flavor relative to the active drug (see, for example, the references Nogelatidi (Nogrady),1985, Medicinal Chemistry: a Biochemical Approach, Oxford university Press, New York, pages 388 to 392, incorporated herein by reference). In addition to the corresponding drugs, prodrugs can be synthesized using the reactants. By way of illustration and not limitation, prodrugs include carboxylate esters, linear and cyclic phosphate esters and phosphoramides and phosphoramidates, carbamates, preferably phenolic carbamates (i.e., carbamates wherein the hydroxy group is part of an aryl or heteroaryl moiety wherein the aryl and heteroaryl groups may be optionally substituted), and the like.

"salt" refers to an ionic compound formed between an acid and a base. When the compounds provided herein contain acidic functional groups, these salts include, but are not limited to, alkali metal, alkaline earth metal, and ammonium salts. Ammonium salts, as used herein, include salts containing protonated nitrogen groups and alkylated nitrogen groups. Illustrative and non-limiting cations suitable for use in pharmaceutically acceptable salts based on naturally occurring amino acids include Na, K, Rb, Cs, NH₄Ca, Ba, imidazolium and ammonium cations. When compounds utilized herein contain basic functional groups, such salts include, but are not limited to, salts of organic acids (e.g., carboxylic acids and sulfonic acids) and inorganic acids (e.g., hydrogen halides, sulfuric acid, phosphoric acid), and the like. Exemplary and non-limiting anions suitable for use in pharmaceutically acceptable salts include oxalate, maleate, acetate, propionate, succinate, tartrate, chloride, sulfate, bisulfate, mono-, di-and trivalent phosphate, methanesulfonate, toluenesulfonate, and the like.

A "therapeutically effective amount" or dose of a compound or composition refers to an amount of the compound or the composition that results in a reduction or inhibition of the symptoms of a patient or an extension of the survival of a patient. The results may require multiple doses of the compound or the composition.

"Treating" or treatment "of a disease in a patient refers to 1) preventing the disease from occurring in a patient predisposed to the disease or not yet exhibiting symptoms of the disease; 2) inhibiting or arresting the development of said disease; or 3) ameliorating the disease or causing regression of the disease. As used herein, "treatment" is a method for obtaining a beneficial or desired result, including a clinical result. For purposes of the present invention, advantageous or desired results include (but are not limited to) one or more of the following: reducing one or more symptoms arising from the disease or disorder, tapering the extent of the disease or disorder, stabilizing the disease or disorder (e.g., preventing or delaying worsening of the disease or disorder), delaying the onset or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, improving the disease or disorder state, providing remission (whether partial or total) of the disease or disorder, reducing the dose of one or more other drugs required to treat the disease or disorder, enhancing the effect of another drug used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life of a patient, and/or prolonging survival of a patient. "treating" also encompasses a reduction in the pathological consequences of the disease or disorder. The methods of the invention contemplate any one or more of these aspects of treatment.

An "isotopic isomer" of a compound is one in which one or more atoms of the compound have been replaced with isotopes of those same atoms. For example, where H has been replaced by D or T, or¹²C already¹¹C is replaced by or¹⁴N has already been¹⁵And (4) N replacement. For example, but not limited to, substitution by D may in some instances result in a decrease in metabolic rate and thus an increase in half-life. Replacement of H with T may provide a radioligand that may be useful in binding studies. Using short-lived isotopes¹¹C substitution¹²C may provide a ligand suitable for use in Positron Emission Tomography (PET) scanning. By using¹⁵N substitution¹⁴N is provided by¹⁵NNMR spectroscopy detection/monitoringA compound (I) is provided. E.g. containing-CH₂CH₃Is an isotopic isomer of a compound of (a), but contains-CD₂CD₃Instead of-CH₂CH₃。

Unless a particular isotope of an element is indicated in the formula, the invention includes all isotopologues of the compounds disclosed herein, e.g., deuterated derivatives of the compounds (where H can be a deuterium derivative of the compound)²H, i.e., D). Isotopologues may have isotopic substitutions at any or all positions in the structure, or may have atoms present in natural abundance at any or all positions in the structure.

"stereoisomers" refers to compounds in which the constituent atoms differ in their stereogenic nature (for example, but not limited to, chirality at one or more stereocenters) or are associated with the cis or trans configuration of a carbon-carbon double bond or a carbon-nitrogen double bond. Stereoisomers include enantiomers and diastereomers.

"tautomers" refer to alternative forms of compounds that differ in the position of the proton, such as enol-ketone and imine-enamine tautomers, or tautomeric forms of heteroaryl groups containing ring atoms bonded to the ring-NH-moiety and the ring-N-moiety, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

"alkyl" refers to a monovalent saturated aliphatic hydrocarbon group having 1 to 12 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 6 carbon atoms. For example, the term includes straight or branched chain hydrocarbyl groups, such as methyl (CH)₃-, ethyl (CH)₃CH₂-), n-propyl (CH)₃CH₂CH₂-, isopropyl ((CH)₃)₂CH-), n-butyl (CH)₃CH₂CH₂CH₂-, isobutyl ((CH)₃)₂CHCH₂-, sec-butyl ((CH)₃)(CH₃CH₂) CH-), tert-butyl ((CH-)₃)₃C-), n-pentyl (CH)₃CH₂CH₂CH₂CH₂-) and neopentyl ((CH)₃)₃CCH₂-)。C_xAlkyl refers to an alkyl group having an x number of carbon atoms.

"alkenyl" means having 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably 1 to 2 vinyl groups ((R)) >C＝C<) A straight or branched chain monovalent hydrocarbon group of an unsaturated site. These groups are exemplified by vinyl, allyl and but-3-en-1-yl, for example. Included within the term are cis and trans isomers or mixtures of these isomers. C_xAlkenyl refers to alkenyl having an x number of carbon atoms.

"alkynyl" refers to a straight or branched chain monovalent hydrocarbon radical having from 2 to 6 carbon atoms and preferably from 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C ≡ C-) unsaturation. Examples of these alkynyl groups include ethynyl (-C.ident.CH) and propargyl (-CH)₂C≡CH)。C_xAlkynyl refers to alkynyl groups having x number of carbon atoms.

"substituted alkyl" refers to an alkyl having 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocyclylamino, substituted heterocyclylamino, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, amino, aminocarbonylthio, aminocarbonyl, aminocarbonylthiocarbonyl, aminocarbonyloxy, aminocarbonylthio, aminocarbonylamino, aminocarbonylthio, arylaminocarbonylamino, substituted heteroarylamino, arylamino, heteroarylamino, cycloalkylamino, heteroarylamino, substituted heterocycl, Guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO, hydroxyl ₃H. Warp beamSubstituted sulfonyl groups, sulfonyloxy groups, sulfonylamino groups, thioacyl groups, thiol groups, alkylthio groups, and substituted alkylthio groups, wherein the substituents are as defined herein.

"substituted alkenyl" refers to alkenyl having 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocyclylamino, substituted heterocyclylamino, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, amino, aminocarbonylthio, aminocarbonyl, aminocarbonylthiocarbonyl, aminocarbonyloxy, aminocarbonylthio, aminocarbonylamino, aminocarbonylthio, arylaminocarbonylamino, substituted heteroarylamino, arylamino, heteroarylamino, cycloalkylamino, heteroarylamino, substituted heterocycl, Guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO, hydroxyl ₃H. Substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein and with the proviso that any hydroxy or thiol substitution is not bound to a vinyl (unsaturated) carbon atom.

"substituted alkynyl" refers to alkynyl having 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxyAminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, substituted heterocyclylamino, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, arylthio, substituted heterocyclyloxy, substituted heterocyclyloxy, amino, substituted arylthio, arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylthio, substituted heterocyclyloxy, carboxyl ester, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃H. Substituted sulfonyl, sulfonyloxy, sulfonylamino, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein and with the proviso that any hydroxy or thiol substitution is not bound to an acetylenic carbon atom.

"alkoxy" refers to the group-O-alkyl, wherein alkyl is as defined herein. Alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy and n-pentoxy.

"substituted alkoxy" refers to the group-O- (substituted alkyl), wherein substituted alkyl is as defined herein. Preferred substituted alkyl groups among-O- (substituted alkyl) include halogenated alkyl groups and specifically halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl and the like.

"acyl" refers to the groups H-C (O) -, alkyl-C (O) -, substituted alkyl-C (O) -, alkenyl-C (O) -, substituted alkenyl-C (O) -, alkynyl-C (O) -, substituted alkynyl-C (O) -, cycloalkyl-C (O) -, substituted cycloalkyl-C (O) -, aryl-C (O) -, substituted aryl-C (O) -, heteroaryl-C (O) -, substituted heteroaryl-C (O) -, heterocycle-C (O) -, and substituted heterocycle-C (O) -, wherein alkyl, substituted alkyl, alkenyl, substituted heterocycle-C (O) -, and substituted heterocycle-C (O) -, are substituted Substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Acyl includes "acetyl" CH₃C(O)-。

"acylamino" refers to the group-NR³⁰C (O) alkyl, -NR³⁰C (O) substituted alkyl, -NR³⁰C (O) cycloalkyl, -NR³⁰C (O) substituted cycloalkyl, -NR³⁰C (O) alkenyl, -NR³⁰C (O) substituted alkenyl, alkoxy, substituted alkoxy-NR³⁰C (O) alkynyl, -NR³⁰C (O) substituted alkynyl, -NR³⁰C (O) aryl, -NR³⁰C (O) substituted aryl, -NR³⁰C (O) heteroaryl, -NR³⁰C (O) substituted heteroaryl, -NR³⁰C (O) heterocyclic ring and-NR³⁰C (O) substituted heterocycle, wherein R³⁰Is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or substituted cycloalkyl; and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"acyloxy" refers to the group alkyl-C (O) O-, substituted alkyl-C (O), alkenyl-C (O), O-, substituted alkenyl-C (O), alkynyl-C (O), O-, substituted alkynyl-C (O) O-, aryl-C (O), O-, substituted aryl-C (O), O-, cycloalkyl-C (O), O-, substituted cycloalkyl-C (O), O-, heteroaryl-C (O), O-, substituted heteroaryl-C (O), O-, heterocycle-C (O) O-, and substituted heterocycle-C (O), wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, Alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"amino" refers to the group-NH₂。

"substituted amino" refers to the groupgroup-NR³¹R³²Wherein R is³¹And R³²Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, arylamine, substituted arylamine, heteroarylamine, substituted heteroarylamine, cycloalkylamine, substituted cycloalkylamine, heterocycloalkylamino, substituted heterocyclylamino, sulfonylamine, and substituted sulfonyl and wherein R is a radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, heteroaryl, substituted heteroaryl, substituted heterocycle, arylamine, substituted arylamine, heteroarylamine, substituted heteroarylamine, cycloalkylamine, substituted cycloalkylamine, heterocyclylamino, substituted heterocyclylamino, sulfonylamine, and substituted sulfonyl ³¹And R³²Optionally linked together with the nitrogen to which they are bound to form a heterocyclic or substituted heterocyclic group, with the proviso that R³¹And R³²Both are not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. When R is³¹Is hydrogen and R³²When alkyl, the substituted amine group is sometimes referred to herein as an alkylamino group. When R is³¹And R³²When alkyl, the substituted amine group is sometimes referred to herein as a dialkylamino group. When referring to a monosubstituted amine group, it means R³¹Or R³²Are hydrogen but not both. When referring to disubstituted amino, it means R³¹Or R³²Neither is hydrogen.

"aminocarbonyl" refers to the group-C (O) NR³³R³⁴Wherein R is³³And R³⁴Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is ³³And R³⁴Optionally linked together with the nitrogen to which they are bound to formHeterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminothiocarbonyl" refers to the group-C (S) NR³³R³⁴Wherein R is³³And R³⁴Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is³³And R³⁴Optionally linked together with the nitrogen to which they are bound to form a heterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminocarbonylamino" refers to the group-NR³⁰C(O)NR³³R³⁴Wherein R is³⁰Is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or substituted cycloalkyl, and R³³And R³⁴Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is³³And R³⁴Optionally linked together with the nitrogen to which they are bound to form a heterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkyneThe group, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminothiocarbonylamino" refers to the group-NR³⁰C(S)NR³³R³⁴Wherein R is³⁰Is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or substituted cycloalkyl, and R ³³And R³⁴Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is³³And R³⁴Optionally linked together with the nitrogen to which they are bound to form a heterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminocarbonyloxy" refers to the group-O-C (O) NR³³R³⁴Wherein R is³³And R³⁴Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is ³³And R³⁴Optionally linked together with the nitrogen to which they are bound to form a heterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminosulfonyl" refers to the group-SO₂NR³³R³⁴Wherein R is³³And R³⁴Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is³³And R³⁴Optionally linked together with the nitrogen to which they are bound to form a heterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminosulfonyloxy" refers to the group-O-SO₂NR³³R³⁴Wherein R is³³And R³⁴Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is³³And R³⁴Optionally linked together with the nitrogen to which they are bound to form a heterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Aminosulfonylamino" refers to the group-NR³⁰-SO₂NR³³R³⁴Wherein R is³⁰Is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl or substituted cycloalkyl, and R³³And R³⁴Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is ³³And R³⁴Optionally linked together with the nitrogen to which they are bound to form a heterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"amidino" refers to the group-C (═ NR)³⁵)NR³³R³⁴Wherein R is³³、R³⁴And R³⁵Is independently selected from the group consisting of: hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle, and wherein R is³³And R³⁴Optionally linked together with the nitrogen to which they are bound to form a heterocycle or substituted heterocyclyl, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"aryl" or "Ar" refers to a monovalent aromatic carbocyclic group having 6 to 14 carbon atoms, having a single ring (e.g., phenyl (Ph)) or multiple condensed rings (e.g., naphthyl or anthracenyl) which may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-1, 4-benzoxazin-3 (4H) -one-7-yl, etc.), provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

"is substitutedThe "aryl group of (a)" means an aryl group substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of: alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, arylamino, substituted arylamino, heteroarylamino, substituted heteroarylamino, cycloalkylamino, substituted cycloalkylamino, heterocycloalkylamino, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, Cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cycloalkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO, or a salt thereof ₃H. Substituted sulfonyl groups, sulfonyloxy groups, sulfonylamino groups, thioacyl groups, thiol groups, alkylthio groups, and substituted alkylthio groups, wherein the substituents are as defined herein.

"aryloxy" refers to the group-O-aryl, wherein aryl is as defined herein, including, for example, phenoxy and naphthoxy.

"substituted aryloxy" refers to the group-O- (substituted aryl), wherein substituted aryl is as defined herein.

"Arylthio" refers to the group-S-aryl, wherein aryl is as defined herein.

"substituted arylthio" refers to the group-S- (substituted aryl) wherein substituted aryl is as defined herein.

"arylamino group"Refers to the group-NR³⁷(aryl) wherein aryl is as defined herein and R³⁷Is hydrogen, alkyl or substituted alkyl.

"substituted arylamino" refers to the group-NR³⁷(substituted aryl) wherein R³⁷Is hydrogen, alkyl or substituted alkyl, wherein substituted aryl is as defined herein.

"carbonyl" refers to the divalent group-C (O) -, which is equivalent to-C (═ O) -.

"carboxy" means-COOH or a salt thereof.

"Carboxylic ester" or "carboxylate" refers to the group-C (O) O-alkyl, -C (O) O-substituted alkyl, -C (O) O-alkenyl, -C (O) O-substituted alkenyl, -C (O) O-alkynyl, -C (O) O-substituted alkynyl, -C (O) O-aryl, -C (O) O-substituted aryl, -C (O) O-cycloalkyl, -C (O) O-substituted cycloalkyl, -C (O) O-heteroaryl, -C (O) O-substituted heteroaryl, -C (O) O-heterocycle, and-C (O) O-substituted heterocycle, where alkyl, substituted alkyl, alkenyl, and C (O) O-substituted heterocycle are substituted, Substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"(carboxy ester) amino" means the group-NR³⁰-C (O) O-alkyl, -NR³⁰-C (O) O-substituted alkyl, -NR³⁰-C (O) O-alkenyl, -NR³⁰-C (O) O-substituted alkenyl, -NR³⁰-C (O) O-alkynyl, -NR³⁰-C (O) O-substituted alkynyl, -NR³⁰-C (O) O-aryl, -NR³⁰-C (O) O-substituted aryl, -NR³⁰-C (O) O-cycloalkyl, -NR³⁰-C (O) O-substituted cycloalkyl, -NR³⁰-C (O) O-heteroaryl, -NR³⁰-C (O) O-substituted heteroaryl, -NR³⁰-C (O) O-heterocycle and-NR³⁰-C (O) O-substituted heterocycle, wherein R³⁰Is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"(carboxy ester) oxy" means the group-O-C (O) O-alkyl, -O-C (O) O-substituted alkyl, -O-C (O) O-alkenyl, -O-C (O) O-substituted alkenyl, -O-C (O) O-alkynyl, -O-C (O) O-substituted alkynyl, -O-C (O) O-aryl, -O-C (O) O-substituted aryl, -O-C (O) O-cycloalkyl, -O-C (O) O-substituted cycloalkyl, -O-C (O) O-heteroaryl, -O-C (O) -substituted heteroaryl, -O-C (O) O-heterocycle and-O-C (O) O-substituted cycloalkyl Substituted heterocycles, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"cyano" refers to the group-C.ident.N.

"cycloalkyl" refers to saturated or unsaturated but non-aromatic cycloalkyl groups having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms, having monocyclic or polycyclic rings, including fused, bridged, and spiro ring systems. C_xCycloalkyl refers to cycloalkyl groups having an x number of ring carbon atoms. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. One or more of the rings can be aryl, heteroaryl, or heterocyclic, provided that the point of attachment saturates the carbocyclic ring through a non-aromatic, non-heterocyclic ring. "substituted cycloalkyl" refers to a cycloalkyl group having 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of: oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, cycloalkylthio, substituted cyclic ring oxy, cycloalkyl thio, substituted cyclic ring oxy, substituted cyclic alkyl thio, substituted cyclic alkyl, cyclic Alkylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocycle, substituted heterocycle, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO, or a pharmaceutically acceptable salt thereof₃H. Substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein the substituents are as defined herein.

"Cycloalkoxy" refers to-O-cycloalkyl.

"substituted cycloalkoxy" refers to-O- (substituted cycloalkyl).

"Cycloalkylamino" refers to the group-NR³⁷(cycloalkyl) in which R³⁷Is hydrogen, alkyl or substituted alkyl.

"substituted cycloalkylamino" refers to the group-NR³⁷(substituted cycloalkyl) wherein R³⁷Are hydrogen, alkyl or substituted alkyl and substituted cycloalkyl as defined herein.

"cycloalkylthio" refers to-S-cycloalkyl.

"substituted cycloalkylthio" refers to-S- (substituted cycloalkyl).

"guanidino" refers to the group-NHC (═ NH) NH₂。

"substituted guanidino" refers to-NR³⁶C(＝NR³⁶)N(R³⁶)₂Wherein each R³⁶Is independently selected from the group consisting of: two R's of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle bound to a common guanidinium nitrogen atom ³⁶The groups are optionally linked together with the nitrogen to which they are bound to form a heterocyclic or substituted heterocyclic group, with the proviso that at least one R³⁶Is other than hydrogen, and wherein the substituents are as defined herein.

"halo" or "halogen" refers to fluoro, chloro, bromo and iodo and is preferably fluoro or chloro.

"hydroxy" refers to the group-OH.

"Heteroalkylene" means a group in which one or more carbons is replaced by-O-, -S-, or SO₂、-NR^Q-、OrPartially substituted alkylene group, wherein R^QIs H or C₁-C₆An alkyl group. "substituted alkylene" refers to an alkylene having 1 to 3 substituents (and preferably 1 to 2 substituents) selected from those disclosed for substituted alkylene.

"heteroaryl" refers to an aromatic group having from 1 to 10 carbon atoms in the ring and from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. These heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain heteroatoms, provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N → O), sulfinyl, or sulfonyl moiety. Preferred heteroaryl groups include 5-or 6-membered heteroaryl groups, such as pyridyl, pyrrolyl, thienyl and furyl. Other preferred heteroaryl groups include 9-or 10-membered heteroaryl groups, such as indolyl, quinolinyl, quinolinonyl, isoquinolinyl and isoquinolinyl groups.

"substituted heteroaryl" refers to heteroaryl substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the same group of substituents defined for substituted aryl.

"heteroaryloxy" refers to-O-heteroaryl.

"substituted heteroaryloxy" refers to the group-O- (substituted heteroaryl).

"heteroarylthio" means the group-S-heteroaryl.

"substituted heteroarylthio" refers to the group-S- (substituted heteroaryl).

"Heteroarylamino" refers to the group-NR³⁷(heteroaryl) wherein R is³⁷Is hydrogen, alkyl or substituted alkyl.

"substituted heteroarylamino" refers to the group-NR³⁷(substituted heteroaryl) wherein R³⁷Are hydrogen, alkyl or substituted alkyl and substituted heteroaryl as defined herein.

"Heterocycle" (Heterocycle) "or" heterocyclic "or" heterocycloalkyl "or" heterocyclyl "refers to a saturated or partially saturated, but non-aromatic group having from 1 to 10 ring carbon atoms, preferably from 1 to 8 carbon atoms, and more preferably from 1 to 6 carbon atoms, and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen, preferably from 1 to 3 heteroatoms, and more preferably from 1 to 2 heteroatoms. C_xHeterocycloalkyl refers to a heterocycloalkyl group having x number of ring atoms (including ring heteroatoms). Heterocycles comprise a single ring or multiple fused rings, which include fused, bridged, and spiro ring systems. In fused ring systems, one or more of the rings may be cycloalkyl, aryl or heteroaryl, provided that the point of attachment is through a non-aromatic ring. In one embodiment, the nitrogen and/or sulfur atoms of the heterocyclyl are optionally oxidized to provide N-oxide, sulfinyl, sulfonyl moieties.

"Heterocyclyl" refers to a divalent saturated or partially saturated, but non-aromatic group having 1 to 10 ring carbon atoms and 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen. "substituted heterocyclylene" refers to a heterocyclylene group substituted with 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

"substituted heterocycle" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to a heterocyclyl group that is substituted with 1 to 5, or preferably 1 to 3, of the same substituents as defined for substituted cycloalkyl.

"heterocyclyloxy" refers to the group-O-heterocyclyl.

"substituted heterocyclyloxy" refers to the group-O- (substituted heterocyclyl).

"Heterocyclylthio" means the group-S-heterocyclyl.

"substituted heterocyclylthio" refers to the group-S- (substituted heterocyclyl).

"Heterocyclylamino" means the group-NR³⁷(heterocyclic group) wherein R is³⁷Is hydrogen, alkyl or substituted alkyl.

"substituted heterocyclylamino" refers to the group-NR³⁷(substituted heterocyclic group), wherein R³⁷Are hydrogen, alkyl or substituted alkyl and substituted heterocyclyl as defined herein.

Examples of heterocyclyl and heteroaryl groups include, but are not limited to, azetidinyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, indolyl, indolinyl, indazolyl, purinyl, quinolyl, isoquinolyl, quinolyl, phthalazinyl, naphthylpyridyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, acridinyl, phenanthridinyl, isothiazolyl, phenazinyl, isoxazolyl, phenoxazinyl, phenothiazinyl, imidazopyridinyl, imidazolinyl, piperidinyl, piperazinyl, indolinyl, phthalimidyl, 1,2,3, 4-tetrahydroisoquinolinyl, 4,5,6, 7-tetrahydrobenzo [ b ] thienyl, thiazolyl, thiazolidinyl, thienyl, benzo [ b ] thienyl, morpholinyl, thiazolidinyl, pyridazinyl, cinnolinyl, pterinyl, carbazolyl, phenanthrolinyl, 1,2,3,4, 5,6, thiomorpholinyl (also known as thiomorpholinyl), 1-dioxothiomorpholinyl, piperidinyl, pyrrolidinyl, and tetrahydrofuranyl.

"Nitro" means the radical-NO₂。

"oxo" refers to an atom (═ O) or (O).

"Spiro ring system" refers to bicyclic ring systems having a single ring carbon atom common to both rings.

"sulfinyl" refers to the divalent group-S (O) -or-S (═ O) -.

"Sulfonyl" refers to a divalent group-S (O)₂-or-S (═ O)₂-。

"substituted sulfonyl" refers to the group-SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-OH、-SO₂-alkenyl, -SO₂-substituted alkenyl, -SO₂-cycloalkyl, -SO₂-substituted cycloalkyl, -SO₂-aryl radical、-SO₂-substituted aryl, -SO₂-heteroaryl, -SO₂-substituted heteroaryl, -SO₂-heterocycle, -SO₂-substituted heterocycle, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Substituted sulfonyl groups include, for example, methyl-SO₂-, phenyl-SO₂-and 4-methylphenyl-SO₂-a group of (a). -SO₂Preferred substituted alkyl groups on substituted alkyl groups include halogenated alkyl groups and in particular halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl and the like.

"substituted sulfinyl" refers to the group-SO-alkyl, -SO-substituted alkyl, -SO-alkenyl, -SO-substituted alkenyl, -SO-cycloalkyl, -SO-substituted cycloalkyl, -SO-aryl, -SO-substituted aryl, -SO-heteroaryl, -SO-substituted heteroaryl, -SO-heterocycle, -SO-substituted heterocycle, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein. Substituted sulfinyl groups include groups such as methyl-SO-, phenyl-SO-, and 4-methylphenyl-SO-. Preferred substituted alkyl groups on substituted alkyl-SO-include halogenated alkyl groups and specifically halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl and the like.

"Sulfonyloxy" or "substituted sulfonyloxy" refers to the group-OSO₂-alkyl, -OSO₂-substituted alkyl, -OSO₂-OH、-OSO₂-alkenyl, -OSO₂-substituted alkenyl, -OSO₂-cycloalkyl, -OSO₂-substituted cycloalkyl, -OSO₂-aryl, -OSO₂-substituted aryl, -OSO₂-heteroaryl, -OSO₂-substituted heteroaryl, -OSO₂-heterocyclic ring, -OSO₂Substituted heterocycles, where alkyl is substitutedAlkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"Sulfonylamino" refers to the group-NR³⁷(substituted sulfonyl) wherein R³⁷Are hydrogen, alkyl or substituted alkyl and substituted sulfonyl as defined herein.

"Thioylyl" refers to the groups H-C (S) -, alkyl-C (S) -, substituted alkyl-C (S) -, alkenyl-C (S) -, substituted alkenyl-C (S) -, alkynyl-C (S) -, substituted alkynyl-C (S) -, cycloalkyl-C (S) -, substituted cycloalkyl-C (S) -, aryl-C (S) -, substituted aryl-C (S) -, heteroaryl-C (S) -, substituted heteroaryl-C (S) -, heterocycle-C (S) -, and substituted heterocycle-C (S) -, wherein alkyl, substituted alkyl, alkenyl, substituted alkynyl-C (S) -, and substituted heterocycle-C (S) -, wherein, Alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle are as defined herein.

"mercapto" or "thiol" refers to the group-SH.

"formyl" refers to the group-C (O) H.

"thiocarbonyl" refers to the divalent group-C (S) -, which is equivalent to-C (═ S) -.

"thione" refers to an atom (═ S).

"alkylthio" refers to the group-S-alkyl, wherein alkyl is as defined herein.

"substituted alkylthio" refers to the group-S- (substituted alkyl) wherein substituted alkyl is as defined herein. Preferred substituted alkyl groups on the-S- (substituted alkyl) include halogenated alkyl groups and specifically halogenated methyl groups such as trifluoromethyl, difluoromethyl, fluoromethyl and the like.

"vinyl" refers to an unsaturated hydrocarbyl group-CH ═ CH derived from ethylene₂。

The terms "optional" or "optionally" as used throughout the specification means that the subsequently described event or circumstance may occur, but does not necessarily occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a nitrogen atom is optionally oxidized to provide an N-oxide (N → O) moiety" means that the nitrogen atom can be oxidized but not necessarily oxidized, and the description includes the case where the nitrogen atom is not oxidized and the case where the nitrogen atom is oxidized.

The term "optionally substituted" refers to a substituted or unsubstituted group. The substituted group may be substituted with one or more substituents, for example, 1, 2, 3, 4, or 5 substituents. Preferably, the substituents are selected from the functional groups provided herein. In certain more preferred embodiments, the substituent is selected from oxo, halo, -CN, NO₂、-CO₂R¹⁰⁰、-OR¹⁰⁰、-SR¹⁰⁰、-SOR¹⁰⁰、-SO₂R¹⁰⁰、-NR¹⁰¹R¹⁰²、-CONR¹⁰¹R¹⁰²、-SO₂NR¹⁰¹R¹⁰²、C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, -CR¹⁰⁰＝C(R¹⁰⁰)₂、-CCR¹⁰⁰、C₃-C₁₀Cycloalkyl radical, C₄-C₁₀Heterocyclic group, C₆-C₁₄Aryl and C₅-C₁₂Heteroaryl, wherein each R¹⁰⁰Independently is hydrogen or C₁-C₈An alkyl group; c₃-C₁₂A cycloalkyl group; c₄-C₁₀A heterocyclic group; c₆-C₁₄An aryl group; or C₂-C₁₂A heteroaryl group; wherein each alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 3 halo, 1 to 3C₁-C₆Alkyl, 1 to 3C₁-C₆Haloalkyl or 1 to 3C₁-C₆Alkoxy substitution. More preferably, the substituents are selected from the group consisting of: chloro, fluoro, -OCH₃Methyl, ethyl, isopropyl, cyclopropyl, -OCF₃、-CF₃and-OCHF₂。

R¹⁰¹And R¹⁰²Independently is hydrogen; optionally via-CO₂H orEster-substituted C thereof₁-C₈Alkyl radical, C₁-C₆Alkoxy, oxo, -CR¹⁰³＝C(R¹⁰³)₂、-CCR、C₃-C₁₀Cycloalkyl radical, C₃-C₁₀Heterocyclic group, C₆-C₁₄Aryl or C₂-C₁₂Heteroaryl, wherein each R¹⁰³Independently is hydrogen or C₁-C₈An alkyl group; c₃-C₁₂A cycloalkyl group; c₄-C₁₀A heterocyclic group; c₆-C₁₄An aryl group; or C₂-C₁₂A heteroaryl group; wherein each cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with 1 to 3 alkyl groups or 1 to 3 halo groups, or R ¹⁰¹And R¹⁰²Together with the nitrogen atom to which they are attached form a 5-to 7-membered heterocyclic ring.

Unless otherwise indicated herein, the nomenclature of substituents not specifically defined herein is achieved by naming the terminal portion of the functional group, followed by the adjacent functional group toward the point of attachment. For example, the substituent "alkoxycarbonylalkyl" refers to the group (alkoxy) -C (O) - (alkyl) -.

It is to be understood that among all substituted groups defined above, polymers achieved by defining substituents with other substituents on their own (e.g., substituted aryl groups having a substituted aryl group as a substituent, substituted aryl groups themselves substituted with a substituted aryl group, etc.) are not intended to be included herein. In these cases, the maximum number of these substituents is three. That is, each of the above definitions is constrained by limitations such as, for example, substituted aryl limited to-substituted aryl- (substituted aryl) -substituted aryl.

It is to be understood that the above definitions are not intended to include impermissible substitution patterns (e.g., substitution of methyl groups with 4 fluoro groups). These impermissible substitution patterns are well known to those skilled in the art.

It should be understood that: certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of embodiments with respect to chemical groups represented by variables are expressly included by the present invention and are disclosed herein as if each combination and each combination were individually and expressly disclosed to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). In addition, all subcombinations of the chemical groups recited in the examples describing these variables are also expressly encompassed by the present invention and are disclosed herein as if each and every such subcombination of chemical groups were individually and explicitly disclosed herein.

Compound (I)

In one aspect, provided herein are compounds of formula (I):

or a tautomer or an N-oxide thereof, or an isotopic isomer of each thereof, or a prodrug of each of the foregoing, or a stereoisomer of each of the foregoing, or a pharmaceutically acceptable salt of each of the foregoing, or a solvate of each of the foregoing, wherein:

ring a together with a carbonyl (keto) group within the ring forms a 5-membered heterocyclic ring containing 1 to 3 ring heteroatoms selected from the group consisting of N, O and S, wherein the heterocyclic ring is optionally substituted with 1 to 2 substituents selected from the group consisting of: c₁-C₃Alkyl and C₃-C₄Cycloalkyl, and wherein the carbonyl (ketone) group is not adjacent to an atom bound to X;

R¹is C₁-C₄An alkyl group; c optionally substituted by 1 to 5 halo (preferably fluoro) or hydroxy₁-C₄An alkyl group; c₃-C₅Cycloalkyl, CON (R)¹⁰)₂Or NR¹⁰COR¹⁰Wherein each R¹⁰Independently is C₁-C₃Alkyl or H;

R²is H or C₁-C₃An alkyl group;

l is O, CH₂、S、SO、SO₂、CO、CHF、CF₂、C(R¹¹) CN (e.g. C (Me) CN), CHR¹¹Or C (R)¹¹)R¹¹Wherein each R¹¹C optionally substituted by 1 to 5 halo, preferably fluoro₁-C₂Alkyl, or 2R¹¹The groups together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring;

R³and R⁴Each of which is independently Cl, Br, Me, or ethyl;

R⁵is H, halo, C ₁-C₄Alkyl (preferably CH)₃) Or C₃-C₄Cycloalkyl, or R⁵And R⁴And the intervening atoms together form a 5-to 7-membered cycloalkyl group or a 5-to 7-membered heterocyclic ring containing 1 to 2 ring heteroatoms; and

x is absent (i.e., X is a bond), or O, NR¹²、C(O)NR¹²、NR¹²C(O)、CR¹²R¹²、OCR¹²R¹²、CR¹²R¹²O、NR¹²CR¹²R¹²、CR¹²R¹²NR¹²、SO₂NR¹²Or NR¹²SO₂Wherein each R¹²Independently H or methyl.

In some embodiments, the compound of formula (I) is a pharmaceutically acceptable salt thereof.

In one embodiment, the compound of formula (I) is a compound of formula (IIA):