Substituted pyrazolo[1,5-a]pyridine compounds as RET kinase inhibitors

Abstract

To provide compounds which are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.SOLUTION: Provided herein are compounds of Formula I, and pharmaceutically acceptable salts and solvates thereof.SELECTED DRAWING: None

Description

[Background technology]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 566,093, filed September 29, 2017. No. 62 / 554,817 filed September 6, 2017, and No. 62 / 554,817 filed April 27, 2017. No. 62 / 491,164 filed on January 18, 2017; No. 2 / 447,850, filed October 10, 2016, and No. 62 / 406,252, filed October 10, 2016. Nos. 6,223,199, 6,253,722 and 6,353,737, each of which is incorporated herein by reference in its entirety. do.

[0002] The present disclosure provides novel methods for inhibiting rearranged (RET) kinase during transfection. Compounds, pharmaceutical compositions containing the compounds, methods for making the compounds, and the compounds in therapy More specifically, the present invention relates to the use of RET, including RET-associated diseases and disorders. Substituted pyrazolo[1]nes useful in the treatment and prevention of diseases that can be treated with kinase inhibitors ,5-a]pyridine compounds.

[0003] RET is required for the normal development, maturation, and maintenance of several tissues and cell types. Muller is a single-pass transmembrane receptor that belongs to the tyrosine kinase superfamily. igan,LM,Nature Reviews Cancer,2014,14, 173-186). The extracellular portion of RET kinase contains four kinase domains involved in ligand binding. Citrate-dependent cadherin-like repeats and membrane required for correct folding of the RET extracellular domain The cytoplasmic portion of the receptor contains two tyrosine kinases, one near the cysteine-rich region, and one near the cytoplasmic region. Contains the ze subdomain.

[0004] RET signaling is mediated by glial cell line-derived neurotrophic factor (GDNF) family ligands. It is mediated by the binding of a group of soluble proteins called GFLs, including Neurtree. Also included are rhodopsin (NTRN), artemin (ARTN), and persephin (PSPN) (Arighi et al.,Cytokine Growth Factor Re v., 2005, 16, 441-67). Unlike other receptor tyrosine kinases, RE T does not bind directly to GFLs but binds to additional co-receptors, namely glycosylphosphatidylinositol (GFLs). Four GDNF family receptors-α are tethered to the cell surface by inositol bonds It requires one of the GFRα family members. Members of the Milli then bind to RET and connect it to the lipid roughness where RET signaling occurs. The binary complexes recruit to cholesterol-rich membrane subdomains known as phospholipase C (MPC) complexes. Form.

[0005] Binding of the ligand-co-receptor complex induces RET dimerization and activation on intracellular tyrosine residues. Autophosphorylation recruits adaptor and signaling proteins to initiate multiple downstream pathways Binding of adaptor proteins to these docking sites stimulates Ras-MA Activation of PK and PI3K-Akt / mTOR signaling pathways, or RET-mediated mechanisms We also recruited the CBL family of ubiquitin ligases that function in RET downregulation. Drop.

[0006] Abnormal RET expression and / or activity is associated with different cancers, and irritable bowel syndrome (IBS) ) and other gastrointestinal disorders have been demonstrated. Summary of the Invention

[0007] Currently, substituted pyrazolo[1,5-a]pyridine compounds are inhibitors of RET kinase and are used in cancer These compounds have been found to be useful for treating diseases such as proliferative disorders including

[0008] Thus, a compound of formula I: [ka]

[0009] or a pharmaceutically acceptable salt or solvate thereof, as provided herein, wherein A, B , X 1 , X 2 , X 3 , X 4 and ring D are as defined herein.

[0010] A compound of Formula I or a pharmaceutically acceptable salt thereof, mixed with a pharmaceutically acceptable diluent or carrier. Pharmaceutical compositions, including acceptable salts or solvates, are also provided herein.

[0011] A method for inhibiting cell proliferation in vitro or in vivo, comprising treating cells with an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or Also provided herein are methods comprising contacting a subject with a pharmaceutical composition comprising:

[0012] A method of treating a RET-associated disease or disorder in a patient in need of such treatment. Thus, the patient is administered a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solution thereof. Methods comprising administering a vehicle or pharmaceutical composition as defined herein are also provided herein. Provided in the specification.

[0013] Treating cancer and / or associated with certain cancers in patients in need of such treatment A method of inhibiting metastasis comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. administering an acceptable salt or solvate, or a pharmaceutical composition as defined herein. Also provided herein are methods, including:

[0014] Irritable Bowel Syndrome (IBS) and / or IB in patients requiring such treatment A method for treating pain associated with S, comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein. Also provided herein are methods comprising administering

[0015] Support, including prevention or minimization of gastrointestinal disorders such as diarrhea associated with treatment, including chemotherapy treatment A method of providing therapy to a cancer patient, comprising administering to the patient a therapeutically effective amount of a compound of formula I or administering a pharmaceutically acceptable salt or solvate, or a pharmaceutical composition as defined herein Also provided is a method comprising:

[0016] Compound of formula I or a pharmaceutically acceptable salt or solvent thereof for use in therapy Also provided herein are solutes, or pharmaceutical compositions as defined herein.

[0017] For use in treating cancer and / or inhibiting metastasis associated with certain cancers, an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a compound as defined herein Pharmaceutical compositions as defined herein are also provided.

[0018] 2. A method for treating irritable bowel syndrome (IBS) or pain associated with IBS, comprising administering to a subject a an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or Also provided herein is a pharmaceutical composition as defined above.

[0019] Support, including prevention or minimization of gastrointestinal disorders such as diarrhea associated with treatment, including chemotherapy treatment Also provided are compounds of formula I, or pharmaceutically acceptable salts thereof, for use in providing therapy to cancer patients. Also provided is a compound or solvate thereof, or a pharmaceutical composition as defined herein.

[0020] A compound of formula I or a pharmaceutically acceptable salt thereof for use in inhibiting RET kinase activity. The resulting salts or solvates are also provided herein.

[0021] A compound of formula I or a pharmaceutical composition thereof for use in treating a RET-associated disease or disorder. A commercially acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, is also included in the present invention. provided in the specification.

[0022] In the manufacture of a medicament for the treatment of cancer and / or the inhibition of metastasis associated with certain cancers, an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or Use of the pharmaceutical compositions defined herein is also provided herein.

[0023] In the manufacture of a medicament for the treatment of irritable bowel syndrome (IBS) or pain associated with IBS an effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, Uses of the pharmaceutical compositions defined herein are also provided herein.

[0024] Support, including prevention or minimization of gastrointestinal disorders such as diarrhea associated with treatment, including chemotherapy treatment a compound of formula I as defined herein in the manufacture of a medicament for providing therapy to a cancer patient. or a pharmaceutically acceptable salt or solvate thereof is also provided herein. .

[0025] In the manufacture of a medicament for the inhibition of RET kinase activity, an effective amount of a compound of formula I or or a pharmaceutically acceptable salt or solvate thereof, or for use in a pharmaceutical composition as defined herein. Uses are also provided herein.

[0026] In the manufacture of a medicament for the treatment of a RET-associated disease or disorder, an effective amount of a compound of Formula I or or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein. Uses of the products are also provided herein.

[0027] A method for treating cancer in a patient in need thereof, comprising: (a) detecting a cancer that is associated with a RET gene; The present invention relates to the analysis of the expression or activity or level of the gene, RET kinase, or any of them. (b) determining whether the cancer is associated with a node abnormality (e.g., a RET-associated cancer); and ET gene, RET kinase, or the expression or activity or level of either thereof If the patient is determined to have a RET-associated cancer, the patient may be offered treatment. an amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, Also provided herein are methods comprising administering the composition.

[0028] Cancer (e.g., R with one or more RET inhibitor resistance mutations) in a patient in need thereof (a) a compound of formula I or a pharmaceutical composition thereof for treating a cancer (such as a RET-associated cancer), (b) a physiologically acceptable salt or solvate thereof; and (c) optionally at least one additional therapeutic agent. Also provided herein are pharmaceutical combinations comprising: , a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof and an additional therapeutic agent are administered as separate compositions or for simultaneous, separate, or sequential use for the treatment of cancer. and a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and the amount of the additional therapeutic agent together are effective in treating cancer. Also provided herein are pharmaceutical compositions containing such compounds for the preparation of a medicament for the treatment of cancer. Such combined uses are also provided herein. A commercial package or product containing such a combination as a combined preparation for Also provided herein are products and methods of treating cancer patients in need thereof.

[0029] 1. A method for reversing or preventing acquired resistance to an anti-cancer drug, comprising administering to a subject a therapeutically effective amount of a compound of formula or a pharmaceutically acceptable salt or solvate thereof, Also provided are methods of administering the compound to a patient at risk of developing or having a sexual relationship. In some embodiments, a dose of an anti-cancer agent (e.g., a dose of a compound of Formula I) is administered. or a pharmaceutically acceptable salt or solvate thereof to a patient. simultaneously) to the patient.

[0030] an effective amount of a compound of formula I or 2. A method for treating cancer in an individual, comprising administering to the individual a pharmaceutically acceptable salt or solvate thereof. Also described herein are methods for delaying and / or preventing the development of cancers that are resistant to a drug. Provided.

[0031] 1. A method of treating an individual having cancer who is likely to develop resistance to an anti-cancer drug, (b) before, during, or after administration of an effective amount of an anti-cancer agent; (a) administering an effective amount of a compound of Formula I; Also provided herein are methods that include administering the substance.

[0032] one or more RET inhibitor resistance mutations that increase the resistance of the cancer to the first RET inhibitor ( For example, at amino acid position 804, e.g., V804M, V804L, or V804E and / or one or more RET inhibitor resistance mutations listed in Tables 3 and 4) a method of treating an individual with a RET-associated cancer with a compound selected from the group consisting of ... a compound of formula I or a RET kinase inhibitor thereof Methods are also provided that include administering a pharmaceutically acceptable salt or solvate.

[0033] A method of treating an individual with a RET-associated cancer, comprising administering to said individual a second anti-cancer agent (e.g., a first RE a compound of formula I or a pharmaceutical agent thereof before, during, or after administration of a compound of formula I or a pharmaceutical agent thereof Also provided are methods comprising administering an acceptable salt or solvate of

[0034] A method for treating irritable bowel syndrome (IBS) in a patient in need thereof, comprising: (a) IBS is characterized by an abnormality in the RET gene, RET kinase, or expression of either of them; (b) IBS However, the RET gene, the RET kinase, or the expression or activity of either of them If it is determined that the patient has a dysregulated level of or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof Also provided herein is a method, comprising:

[0035] A therapeutic agent for treating irritable bowel syndrome (IBS) in a patient in need thereof. as separate compositions or dosages for simultaneous, separate, or sequential use for the treatment of (a) a compound of general formula I or a pharmaceutically acceptable salt or solvate thereof, (b) an additional therapeutic agent; and (c) optionally at least one pharmaceutically acceptable carrier. Also provided herein are pharmaceutical combinations comprising administering a compound of Formula I or the amount of the pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent together is I The combination is effective in treating BS. Pharmaceutical compositions containing such combinations are also provided herein. The use of such a combination for the preparation of a medicament for the treatment of IBS is also disclosed herein. As a combined preparation for simultaneous, separate or sequential use. and commercial packages or products containing such combinations, and Methods of treating BS patients are also provided herein.

[0036] Process for preparing a compound of formula I or a pharmaceutically acceptable salt or solvate thereof A method for producing a medicament for the treatment of ...

[0037] A compound of formula I or a compound thereof obtained by the process for preparing the compound defined herein. Also provided herein are pharmaceutically acceptable salts or solvates of:

[0038] Unless otherwise defined, all technical and scientific terms used herein are intended to be used by the present invention. The term "a" has the same meaning as commonly understood by a person skilled in the art. Methods and materials are described herein for use in the present invention and are well known in the art. Other suitable methods and materials known in the art may also be used. Materials, Methods, and Examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references are the property of their respective owners. In case of conflict, the present specification, including definitions, will prevail. Priority shall be given to:

[0039] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. It will become clear from the surroundings. DETAILED DESCRIPTION OF THE INVENTION

[0040] A compound of formula I, [ka]

[0041] and pharmaceutically acceptable salts and solvates thereof, wherein:

[0042] X 1 , X 2 , X 3 , and X 4 are independently CH, CF, CCH3, or N; X 1 , X 2 , X 3 , and X 4 0, 1, or 2 of are N,

[0043] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN, or -CH(CN)CH3,

[0044] B,

[0045] (a) hydrogen,

[0046] (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro;

[0047] (c) hydroxy C2-C6 alkyl-, wherein the alkyl moiety is 1 to 3 fluoro or a hydroxy C2-C optionally substituted with a C3-C6 cycloalkylidene ring. 6 alkyl-,

[0048] (d) dihydroxyC3-C6 alkyl-, wherein the alkyl moiety is C3-C6 cyclo dihydroxyC3-C6 alkyl-, optionally substituted on the alkylidene ring;

[0049] (e) (C1-C6 alkoxy)C1-C6 alkoxy optionally substituted with 1 to 3 fluoro groups kill-,

[0050] (f)(R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH. Converted to R 1 and R 2 are independently H or C1-C6 alkyl (1 to 3 fluoro (R 1 R 2 N) C1-C6 alkyl-,

[0051] (g)hetAr 1 C1-C3 alkyl-, where hetAr 1 But N, O, and S and a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from and optionally substituted with one or more independently selected C1-C6 alkyl substituents; hetAr 1 C1-C3 alkyl-,

[0052] (h) (C3-C6 cycloalkyl)C1-C3 alkyl-, where cycloalkyl is , (C3-C6 cycloalkyl)C1-C3 alkyl-, optionally substituted with OH;

[0053] (i)(hetCyc a ) C1-C3 alkyl-,

[0054] (j)hetCyc a -,

[0055] (k) C3-C6 cycloalkyl-, wherein the cycloalkyl is optionally substituted with OH. C3-C6 cycloalkyl-,

[0056] (l) (C1-C4 alkyl)C(=O)O-C1-C6 alkyl-, where C1-C 4 alkyl moieties and C1-C6 alkyl moieties each optionally and independently have 1 to 3 (C1-C4 alkyl)C(=O)O-C1-C6 alkyl, substituted with fluoro Ru-, or

[0057] (m)(R 1 R 2 N)C(=O)C1-C6 alkyl-, where R 1 and R 2 becomes independent and H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro). , (R 1 R 2 N)C(=O)C1-C6 alkyl-;

[0058] hetCyc a - has 1 to 2 ring heteroatoms independently selected from N and O 4-6 membered heterocyclic ring, optionally containing OH, C1-C6 alkyl (1-3 fluoro) substituted with), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C 6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl-, and optionally substituted with one or more substituents independently selected from the group consisting of fluoro, ... etCyc a is substituted with oxo,

[0059] Ring D is (i) a saturated 4- to 7-membered heterocyclic ring having two ring nitrogen atoms, (ii) a ring a saturated 7-8 membered bridge having a nitrogen atom and, optionally, a third ring heteroatom that is oxygen; heterocyclic ring, (iii) a saturated 7- to 11-membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9- to 10-membered bicyclic fused heterocyclic ring having two ring nitrogen atoms; Each of the rings is (a) a C1- optionally substituted with halogen, OH, 1 to 3 fluoro. C3 alkyl or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from the group consisting of a C3-C6 cycloalkylidene ring, or c) optionally substituted with oxo groups;

[0060] E is,

[0061] (a) hydrogen,

[0062] (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro;

[0063] (c) (C1-C6 alkoxy)C1-C6 alkoxy optionally substituted with 1 to 3 fluoro groups kill-,

[0064] (d) (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is 1 to 3 Fluoro or R g R h N-substituent (wherein R G and R H are independently H or optionally substituted with (C1-C6 alkyl)C(=O )-,

[0065] (e) (hydroxyC2-C6 alkyl)C(= optionally substituted with 1 to 3 fluoro O)-,

[0066] (f) (C1-C6 alkoxy)C(=O)-,

[0067] (g) (C3-C6 cycloalkyl)C(=O)-, wherein the cycloalkyl is C 1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)C1 -C6 alkyl-, or or cycloalkyl has 1 to 3 ring heteroatoms independently selected from N and O (C3-C6 cycloalkyl)C (=O)-,

[0068] (h)Ar 1 C1-C6 alkyl-,

[0069] (i)Ar 1 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is OH , hydroxy C1-C6 alkyl-, C1-C6 alkoxy, R m R n N- or R m R n N-CH2-(in the formula, each R mand R n are independently H or C1-C6 alkyl Optionally substituted with Ar 1 (C1-C6 alkyl)C(=O)-,

[0070] (j)hetAr 2 C1-C6 alkyl-, wherein the alkyl moiety is 1 to 3 fluorines. optionally substituted with Ar 2 C1-C6 alkyl-,

[0071] (k)hetAr 2 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety , optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy HetAr 2 (C1-C6 alkyl)C(=O)-,

[0072] (l)hetAr 2 C(=O)-,

[0073] (m)hetCyc 1 C(=O)-,

[0074] (n)hetCyc 1 C1-C6 alkyl-,

[0075] (o)R 3 R 4 NC(=O)-,

[0076] (p)Ar 1 N(R 3 )C(=O)-,

[0077] (q)hetAr 2 N(R 3 )C(=O)-,

[0078] (r) (C1-C6 alkyl)SO2-, wherein the alkyl portion is 1 to 3 fluoro (C1-C6 alkyl)SO2-, optionally substituted with

[0079] (s)Ar 1 SO2-,

[0080] (t)hetAr 2 SO2-,

[0081] (u) N-(C1-C6 alkyl)pyridinonyl,

[0082] (v)Ar 1 C(=O)-,

[0083] (w)Ar 1 OC(=O)-,

[0084] (x) (C3-C6 cycloalkyl)(C1-C6 alkyl)C(=O)-,

[0085] (y) (C3-C6 cycloalkyl)(C1-C6 alkyl)SO2-, where alkyl is the alkyl moiety is optionally substituted with 1 to 3 fluoro; (C1-C6 alkyl)SO2-,

[0086] (z)Ar 1 (C1-C6 alkyl)SO2-,

[0087] (aa)hetCyc 1 -OC(=O)-,

[0088] (bb)hetCyc 1 CH2C(=O)-,

[0089] (cc)hetAr 2 ,or

[0090] (dd) C3-C6 cycloalkyl;

[0091] Ar 1is optionally substituted with halogen, CN, C1-C6 alkyl (1 to 3 fluoro) C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), R e R f N -(In the formula, R e and R f are independently H, C1-C6 alkyl), (R p R q N ) C1-C6 alkoxy-(wherein R p and R q are independently H or C1-C6 alkyl Kill), and (hetAr a ) C1-C6 alkyl-(wherein, a but, a 5- or 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms, or Ar 1 but, 5- to 6-membered heterocyclic rings having 1 to 2 ring heteroatoms independently selected from N and O is a phenyl ring fused to

[0092] hetAr 2 are independently 1 to 3 ring hetero atoms independently selected from N, O, and S. 5-6-membered heteroaryl ring having 1-3 nitrogen atoms, or 9-1 0-membered bicyclic heteroaryl ring, hetAr 2 But halogen, CN, C1-C6 alkane alkyl (optionally substituted with 1 to 3 fluoro), C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), (C1-C6 alkoxy)C1-C6 alkyl-(1-3 optionally substituted with fluoro) optionally substituted with fluoro, R e R f N-(wherein, R e and R f became independent, H or C1-C6 alkyl), OH, (C1-C6 alkoxy)C1-C6 alkoxy one or more independently selected from the group consisting of koxy-, and C3-C6 cycloalkyl and optionally substituted with a substituent of

[0093] hetCyc 1 is 1 to 2 ring heteroatoms independently selected from N, O, and S and the heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having the formula optionally substituted with one or more substituents independently selected from

[0094] R 3 is H or C1-C6 alkyl;

[0095] R 4 is C1-C6 alkyl, as well as pharmaceutically acceptable salts and and solvates are provided herein.

[0096] For complex chemical names used herein, a substituent is named before the group to which it is attached. For example, methoxyethyl contains an ethyl skeleton with a methoxy substituent.

[0097] The term "halogen" refers to -F (referred to herein as "fluoro" or or "fluoros"), -Cl, -Br, and -I.

[0098] As used herein, "C1-C3 alkyl," "C1-C6 alkyl," "C2-C6 The terms "C3-C6 alkyl" and "C3-C6 alkyl" refer to 1 to 3 and 1 to 6 alkyl groups, respectively. a saturated straight-chain or branched-chain monovalent hydrocarbon radical of 2 to 6, or 3 to 6 carbon atoms Examples include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, and isobutyl. butyl, sec-butyl, tert-butyl, 2-methyl-2-propyl, pentyl, neo Examples include, but are not limited to, pentyl, and hexyl.

[0099] As used herein, the term "C1-C6 alkoxy" refers to a radical having an alkyl group attached to an oxygen atom. A saturated straight- or branched-chain monovalent alkoxy radical of 1 to 6 carbon atoms. Examples include Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, and tert -butoxy.

[0100] As used herein, "(C1-C6 alkoxy)C1-C6 alkyl-" and "( The term "C1-C6 alkoxy)C2-C6 alkyl-" means that one of the carbon atoms is each substituted with 1 to 6 C1-C6 alkoxy groups as defined in the specification A saturated straight- or branched-chain monovalent radical of 1 carbon atom or 2 to 6 carbon atoms. Examples include Examples include methoxymethyl (CH3OCH2-) and methoxyethyl (CH3OCH2C H2-).

[0101] As used herein, "hydroxyC1-C6 alkyl-" and "hydroxyC2-C The term "6 alkyl-" refers to a group in which one of the carbon atoms is substituted with a hydroxy group. saturated straight-chain or branched-chain monovalent alkyl radicals of 1 to 6 or 2 to 6 carbon atoms, respectively Refers to the rule.

[0102] As used herein, the term "dihydroxyC3-C6 alkyl-" refers to a group of carbon atoms saturated straight or branched chain of 3 to 6 carbon atoms, two of which are substituted with hydroxy groups Refers to a branched-chain monovalent alkyl radical.

[0103] As used herein, "(R 1 R 2 N)C1-C6 alkyl-" and "(R 1 R 2 N) The term "C2-C6 alkyl-" refers to a group in which one of the carbon atoms is R 1 R 2 N-substituted Re, R 1 and R 2 is as defined herein, refers to a C1-C6 alkyl or C2-C6 radical, respectively.

[0104] As used herein, "hetAr" 1 The term "C1-C6 alkyl-" refers to the carbon atoms One of them is hetAr 1 Substituted with a group, hetAr 1 is defined herein "C1-C6 alkyl radical" refers to a C1-C6 alkyl radical as defined herein, wherein

[0105] As used herein, the term "C3-C6 cycloalkyl" includes cyclopropyl, Refers to cyclobutyl, cyclopentyl, or cyclohexyl.

[0106] As used herein, "(C3-C6 cycloalkyl)C1-C3 alkyl-" and " The term (C3-C6 cycloalkyl)C1-C6 alkyl- means any one of the carbon atoms. substituted with a C3-C6 cycloalkyl ring as defined herein. a C1-C3 alkyl radical, or a C1-C6 radical, respectively, as defined in the document. He points to Cal.

[0107] As used herein, the term "C3-C6 cycloalkylidene ring" refers to a ring having 3 to 6 The suffix "iridine" refers to two carbocyclic rings from the same carbon atom. refers to a divalent radical derived from a saturated hydrocarbon by removal of a hydrogen atom.

[0108] As used herein, "(hetCyc a The term "C1-C3 alkyl-" refers to One of the atoms is hetCyc a Substituted with hetCyc a In this specification, refers to a C1-C3 alkyl radical as defined herein, as defined vinegar.

[0109] As used herein, "Ar 1 The term "C1-C6 alkyl-" refers to any of the carbon atoms One is Ar 1 substituted with Ar 1 is as defined herein. refers to a C1-C6 alkyl radical as defined in the document.

[0110] As used herein, "hetAr" 2 The term "C1-C6 alkyl-" refers to the carbon atoms One of them is hetAr 2 Substituted with a group, hetAr 2 is defined herein as "C1-C6 alkyl" refers to a C1-C6 alkyl radical as defined herein.

[0111] As used herein, "hetCyc" 1 The term "C1-C6 alkyl-" refers to the carbon atoms One of them is hetCyc 1 Substituted with hetCyc 1 is defined herein "C1-C6 alkyl" refers to a C1-C6 alkyl radical as defined herein, as defined herein.

[0112] As used herein, the term "N-(C1-C6 alkyl)pyridinonyl" refers to a ring The nitrogen atom is substituted with a C1-C6 alkyl substituent and the radical is a carbon atom other than the carbon bearing an oxo group. The pyridin-2(1H)-one ring may have any of the ring carbon atoms: Examples include the following structures: [ka]

[0113] As used herein, the term "heterospirocyclic ring" refers to a spirocyclic ring formed via a carbon atom. are joined by cyclic bonds, each ring having 4 to 6 ring atoms (wherein one ring carbon atom is a group having two rings, two of the ring atoms being nitrogen atoms, Refers to...

[0114] The term "oxo" or "oxo group" as used herein means a double bond to a carbon atom. For example, in one embodiment, the reference to ring D is Then, a saturated 6-membered heterocyclic ring having two ring nitrogen atoms can be substituted with, for example, an oxo group. The piperazinyl ring may be a piperazinyl ring (e.g., a piperazinyl ring) which can be represented by the following structure: It can be expressed as: [ka]

[0115] As used herein, the term "compound" includes all stereoisomers, geometrical isomers, and / or derivatives of the depicted structure. It is intended to include all isomers, tautomers, and isotopes. Compounds herein identified by name or structure as compounds of the present invention are , and other tautomeric forms are intended to be included.

[0116] As used herein, the term "tautomer" refers to a compound that has a distinct arrangement of atoms, refers to compounds that exist in a state of ready and rapid equilibrium, and the compounds provided herein are When a compound has tautomeric forms, all tautomeric forms are Tautomeric forms are intended to be within the scope of the present invention, and the naming of the compounds does not include any tautomeric forms. It should be understood that this does not exclude tautomerizations. Exemplary tautomerizations include keto to enol, Amides to imides, lactams to lactims, enamines to imines, and enamines These include, but are not limited to, tautomerization from pheno to (different) enamine. A specific example of tautomerization of pyridine-keto is pyridine-2-ol and pyridine-2-ol. Interconversion with the (1H)-one tautomer. [ka]

[0117] Certain compounds provided herein may contain one or more asymmetric centers, It can therefore be prepared and used in a racemic mixture, a mixture of isomers, or in enantiomerically pure form. It will be understood that the compound may be isolated.

[0118] In certain embodiments of formula I, X 1 , X 2 , X 3 , and X 4 are independent, CH , CF, or CCH3. In certain embodiments, X 1 , X 2 , X 3, and X 4 Each of the is CH.

[0119] In certain embodiments of formula I, X 1 , X 2 , X 3 , and X 4 are independent, CH , CF, or CCH3 or N, and X 1 , X 2 , X 3 , and X 4 One of is N and the remainder are independently CH, CF, or CCH3. Certain embodiments of Formula I In the embodiment, X 1 is N and X 2 , X 3 , and X 4 are independently CH or CF In certain embodiments, X 1 is N and X 2 , X 3 , and X 4 is C H. In certain embodiments, X 1 is N and X 2 is CF and X 3 Oh and X 4 is CH.

[0120] In certain embodiments of formula I, X 1 , X 2 , X 3 , and X 4 are independent, CH , CF, or CCH3 or N, and X 1 , X 2 , X 3 , and X 4 Two of is N. In certain embodiments of Formula I, X 1 and X 3 is N and X 2 oh Call X 4is independently CH, CF, or CCH. In one embodiment, X 1 oh Call X 3 is N and X 2 and X 4 is CH. In certain embodiments of Formula I, X 1 and X 2 is N and X 1 and X 4 are independently CH or CF In certain embodiments of formula I, X 1 and X 2 is N and X 1 and X 4 teeth , CH.

[0121] In certain embodiments of formula I, A is H.

[0122] In certain embodiments of formula I, A is Cl.

[0123] In certain embodiments of formula I, A is CN.

[0124] In certain embodiments of formula I, A is CH3-.

[0125] In certain embodiments of Formula I, A is CH3CH2-.

[0126] In certain embodiments of formula I, A is cyclopropyl.

[0127] In certain embodiments of formula I, A is -CH2CN.

[0128] In certain embodiments of formula I, A is —CH(CN)CH 3 .

[0129] In certain embodiments of formula I, B is hydrogen.

[0130] In certain embodiments of formula I, B is C optionally substituted with 1 to 3 fluoro. 1-C6 alkyl. Non-limiting examples include methyl, ethyl, propyl, isopropyl Pyr, isobutyl, 2-methylbutyl, 2-ethylbutyl, 2,2-dimethylpropyl, Difluoromethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl Examples include:

[0131] In certain embodiments of formula I, B is hydroxyC2-C6 alkyl- The alkyl portion is optionally substituted with 1 to 3 fluoro or C3-C6 cycloalkylidene rings. In certain embodiments of Formula I, wherein B is hydroxyC2-C6 alkyl-, and the alkyl moiety is substituted. Non-limiting examples include the following structures: [ka]

[0132] In certain embodiments of Formula I, B is dihydroxyC3-C6 alkyl- and the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. In certain embodiments of Formula I, B is a dihydrogen group. Non-limiting examples include 2,3-dihydroxypropyl, 2,3-dihydroxypropyl, and 2,3-dihydroxypropyl. Includes:

[0133] In certain embodiments of Formula I, B is optionally substituted with 1-3 fluoro ( In certain embodiments of Formula I, and B is (C1-C6 alkoxy)C2-C6 optionally substituted with 1 to 3 fluoro. Non-limiting examples include the following structures: [ka]

[0134] In certain embodiments of formula I, B is (R 1 R 2 N) C1-C6 alkyl- wherein the alkyl moiety is optionally substituted with OH, and R 1 and R 2 are independently H or is C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), (R 1 R 2 N )C1-C6 alkyl-. In certain embodiments of Formula I, B is (R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH; R 1 and R 2 are independently H or C2-C6 alkyl (optionally substituted with 1 to 3 fluoro (R 1 R 2 N) C1-C6 alkyl-. Certain embodiments of Formula I In this state, B is (R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl moiety is , optionally substituted with OH, and R 1 and R 2 are independently H or C1-C6 alkyl substituted (R 1 R 2 N)C1-C6 alkyl-. B is (R 1 R 2 N )C1-C6 alkyl-, non-limiting examples include the following structures: [ka]

[0135] In certain embodiments of formula I, B is hetAr 1 C1-C3 alkyl- Te, hetAr 1 is 1 to 3 ring heteroatoms independently selected from N, O, and S and one or more independently selected C1-C6 alkyl groups. optionally substituted with alkyl substituents, 1 It is C1-C3 alkyl-. In certain embodiments, hetAr 1 are 1 to 3 independently selected from N and O and optionally C1-C6 alkyl. It has been replaced. 1 Non-limiting examples of C1-C3 alkyl- include the following structures: nothing. [ka]

[0136] In certain embodiments of formula I, B is (C3-C6 cycloalkyl)C1-C3 alkyl-, wherein the cycloalkyl is optionally substituted with OH, (C3-C 6 cycloalkyl)C1-C3 alkyl-. Non-limiting examples include the following structures: [ka]

[0137] In certain embodiments of Formula I, B is (hetCyc a )C1-C3 alkyl- and hetCyc a is 1 to 2 ring heteroatoms independently selected from N and O OH, C1-C6 alkyl (1-3 fluoro) optionally substituted), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1 -C6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl-, and and fluoro; hetCyc a is substituted with oxo. Non-limiting examples include the following structures: [ka] [ka]

[0138] In certain embodiments of Formula I, B is hetCyc a and hetCyc a but , a 4- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O a ring, optionally substituted with OH, C1-C6 alkyl (optionally substituted with 1-3 fluoro), hydroxy C1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(=O )-, (C1-C6 alkoxy)C1-C6 alkyl-, and fluoro; or hetCyca is optionally substituted with one or more substituents selected from the group consisting of oxo, In certain embodiments, hetCyc is substituted with a is OH or C1- Optionally substituted with C6 alkyl (optionally substituted with 1-3 fluoro). Typical examples include the following structures: [ka]

[0139] In certain embodiments of formula I, B is C3-C6 cycloalkyl-, wherein The cycloalkyl is C3-C6 cycloalkyl- optionally substituted with OH. A non-limiting example is the following structure: [ka]

[0140] In certain embodiments of Formula I, B is optionally substituted with 1-3 fluoro ( C1-C4 alkyl)C(=O)O-C1-C6 alkyl-. Non-limiting examples include: The structure is shown below. [ka]

[0141] In certain embodiments of formula I, B is (R 1 R 2 N)C(=O)C1-C6 Al Kill-Because R 1 and R 2 are independently H or C1-C6 alkyl (1 to 3 (R optionally substituted with fluoro) 1 R 2 N)C(=O)C1-C6 alkyl- Non-limiting examples include the following structures: [ka]

[0142] In one embodiment of Formula I, Ring D is (i) a saturated 4- to 7-membered complex having two ring nitrogen atoms. (ii) a heterocyclic ring having two ring nitrogen atoms and, optionally, a third ring heteroatom which is oxygen; (iii) a saturated 7- or 8-membered bridged heterocyclic ring having two ring nitrogen atoms; an 11-membered heterospirocyclic ring, or (iv) a saturated 9- to 10-membered bicyclic ring having two ring nitrogen atoms; cyclic fused heterocyclic rings, each of which is selected from the group consisting of (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with 1 to 3 fluoro; (b) 1 to 4 groups independently selected from C1-C3 alkoxy; a chloroalkylidene ring, or (c) optionally substituted with an oxo group.

[0143] As used herein, the phrase "having two ring nitrogen atoms" when referring to Ring D means The two ring nitrogen atoms of ring D are the two ring nitrogen atoms shown in formula I, One is X 1 , X 2 , X 3 , and X 4 and the other ring nitrogen atom is E It means that it is bonded to the group.

[0144] In one embodiment, ring D is (i) a saturated 4- to 7-membered heterocyclic ring having two ring nitrogen atoms. (ii) a ring having two ring nitrogen atoms and, optionally, a third ring heteroatom that is oxygen; (iii) a saturated 7- to 8-membered bridged heterocyclic ring having two ring nitrogen atoms; heterospirocyclic ring, or (iv) a saturated 9- to 10-membered bicyclic fused ring having two ring nitrogen atoms Heterocyclic rings, each of which is unsubstituted.

[0145] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and the ring is (a) a C1-C optionally substituted with halogen, OH, or 1 to 3 fluoro. 3 alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro (b) 1 to 4 independently selected groups, (c) a C3-C6 cycloalkylidene ring, or As used herein, Ring D is a saturated monocyclic 4- to 7-membered ring optionally substituted with an oxo group. The phrase "having two ring nitrogen atoms" when referring to a heterocyclic ring means that the ring nitrogen atoms are means the two nitrogen atoms shown in ring D of formula I, wherein ring D is represented by the following structure: It can be done, [ka]

[0146] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 The asterisk indicates the point of attachment to the ring containing the The ring A indicates the point of attachment to the E group, and the ring D is (a) any of halogen, OH, and 1 to 3 fluoro. optionally substituted C1-C3 alkyl or C optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from 1-C3 alkoxy; or (c) an oxo group. is an unsubstituted saturated 6-membered heterocyclic ring having two ring nitrogen atoms. Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, and the ring is substituted with oxo. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. and the ring is substituted with a C3-C6 cycloalkylidene ring. wherein ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, and the ring is In one embodiment, ring D is substituted with two C6 cyclopropyl lysine rings. and the ring is a saturated 6-membered heterocyclic ring having a ring nitrogen atom of the formula: C1-C3 alkyl optionally substituted with up to 3 fluoro, or 1 to 3 fluoro and substituted with 1 to 4 groups independently selected from C1-C3 alkoxy optionally substituted with In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. and the ring is substituted with C1-C3 alkyl optionally substituted with 1 to 3 fluoro. In one embodiment, ring D is a saturated 7-membered heterocyclic ring having two ring nitrogen atoms. and the ring is unsubstituted.

[0147] In one embodiment when Ring D is a saturated 6- to 7-membered heterocyclic ring having two ring nitrogen atoms, wherein the ring D and E moieties of formula I are: [ka]

[0148] It may be represented by the following structure: [ka]

[0149] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 and ring D indicates the point of attachment to the ring containing ha halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group In one embodiment, ring D is unsubstituted. D is substituted with oxo. In one embodiment, Ring D is C3-C6 cyclopropyl In one embodiment, ring D is substituted with oxo. In one embodiment, ring D is optionally substituted with halogen, OH, 1-3 fluoro. C1-C3 alkyl or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro In one embodiment, ring D is substituted with 1 to 4 groups independently selected from , a saturated 6-membered heterocyclic ring having two ring nitrogen atoms, the ring containing 1 to 3 fluoro In one embodiment, the alkyl group is substituted with 1 to 4 C1-C3 alkyl groups, each of which is optionally substituted with wherein ring D is unsubstituted or contains 1 to 4 independently selected C1 -C3 alkyl groups, each of which is optionally substituted with 1-fluoro; or Ring D is substituted with a C3-C6 cyclopropyl lysine ring; or Ring D is substituted with oxo. In one embodiment, Ring D has two ring nitrogen atoms. and the ring is unsubstituted. Saturated 6- and 7-membered heterocyclic rings Examples of Formula D rings include the following structures: [ka]

[0150] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) and optionally substituted with an oxo group, and E is as defined for formula I. In the embodiment, ring D is a saturated 6- to 7-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is substituted with oxo. In one embodiment, ring D is substituted with a cyclopropyl lysine ring. In one embodiment, ring D contains one or two C1-C3 alkyl groups, for example, one or or two methyl groups.

[0151] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) and E is optionally substituted with an oxo group, and E is (a) hydrogen, or (c) 1 to 3 fluoro groups. (C1-C6 alkoxy)C1-C6 alkyl- substituted with 1 to 3 fluoro groups; (C1-C6 alkyl)C(=O)- optionally substituted with (e) 1 to 3 fluoro (hydroxyC2-C6)alkyl optionally substituted with)C(=O)-, (f) (C1- (C6 alkoxy)C(=O)-, (g) (C3-C6 cycloalkyl)C(=O)- wherein the cycloalkyl is (C1-C6 alkoxy)C1-C6 alkyl- and optionally substituted or containing 1 to 3 ring heteroatoms independently selected from N and O; (C3-C6 cycloalkyl optionally substituted with a 5-6 membered heteroaryl ring having )C(=O)-, (h)Ar 1 C1-C6 alkyl-, (i) Ar1 (C1-C6 alkyl C(=O)-, wherein the alkyl moiety is OH, hydroxyC1-C6 alkyl -, or optionally substituted with C1-C6 alkoxy, Ar 1 (C1-C6 alkyl )C(=O)-, (J)hetAr 2 C1-C6 alkyl-, the alkyl moiety is optionally substituted with 1 to 3 fluoro, hetAr 2 C1-C6 alkyl-, (K)hetAr 2 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety , optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy HetAr 2 (C1-C6 alkyl)C(=O)-, (l)hetAr 2 C( =O)-, (m)hetCyc 1 C(=O)-, (n)hetCyc 1 C1-C6 alkyl Ru-(o)R 3 R 4 NC(=O)- or (cc)hetAr 2 , and Ar 1 , h etAr 2 , hetCyc 1 , R 3 and R 4 is as defined for Formula I In one embodiment, ring D is a saturated 6- to 7-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is a saturated 7-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is a saturated 6-7 membered heterocyclic ring, and Ring D is unsubstituted. In one embodiment, ring D is a saturated 6-membered ring. In one embodiment, ring D is substituted with a cyclopropyl lysine ring. In one embodiment, Ring D is selected from the group consisting of 1 or 2 C1-C3 alkyl groups, e.g. For example, it is substituted with one or two methyl groups.

[0152] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) In one embodiment, ring D is optionally substituted with an oxo group, and E is hydrogen. In one embodiment, ring D is a substituted 6-membered heterocyclic ring having a ring nitrogen atom of A non-limiting example is the following structure: [ka]

[0153] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) E is optionally substituted with 1 to 3 fluoro groups (C1 In one embodiment, ring D is selected from the group consisting of two alkyl groups. In one embodiment, ring D is a substituted 6-membered heterocyclic ring having a ring nitrogen atom. A non-limiting example is the following structure: [ka]

[0154] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) E is optionally substituted with 1 to 3 fluoro groups (C1 In one embodiment, ring D is a ring having two nitrogen atoms. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having the formula: In one embodiment, Ring D is unsubstituted. A non-limiting example is the following structure: [ka]

[0155] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) E is optionally substituted with 1 to 3 fluoro groups (hydro). In one embodiment, ring D is a C2-C6 alkyl)C(=O)-. In one embodiment, ring D is a substituted 6-membered heterocyclic ring having a ring nitrogen atom. A non-limiting example is the following structure: [ka]

[0156] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is (C1-C6 alkoxy)C(=O)- In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. A non-limiting example is the following structure: [ka]

[0157] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is (C3-C6 cycloalkyl)C(=O)-; wherein the cycloalkyl is (C1-C6 alkoxy)C1-C6 alkyl-, is a 5- to 6-membered heteroaromatic group having 1 to 3 ring heteroatoms independently selected from N and O; (C-C cycloalkyl)C optionally substituted with an aryl ring, e.g., pyridinyl In one embodiment, ring D is a saturated 6-membered ring having two ring nitrogen atoms. In one embodiment, ring D is unsubstituted. Non-limiting examples include: It includes the following structure: [ka]

[0158] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) E is optionally substituted with an oxo group, and Ar 1 C1-C6 alkyl-, Ar 1 is as defined for formula I, Ar 1 C1-C6 alkyl-. In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is substituted with oxo. In one embodiment, Ar 1 is unsubstituted. Non-limiting examples include Includes structure. [ka]

[0159] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) E is optionally substituted with an oxo group, and Ar 1 (C1-C6 alkyl)C(=O)- The alkyl moiety is OH, hydroxy C1-C6 alkyl, C1-C6 alkoxy, Kishi, R m R n N- or R m R n optionally substituted with N-CH2-, and each R m Oh BiR n are independently H or C1-C6 alkyl, and Ar 1 is defined for Formula I As can be seen, Ar 1 (C1-C6 alkyl)C(=O)-. In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. and Ring D is unsubstituted. 1 is not substituted or or substituted with one or more halogens. Non-limiting examples include the following structures: [ka]

[0160] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is a hetAr 2 C1-C6 alkyl- the alkyl moiety is optionally substituted with 1 to 3 fluoro; 2 is the expression as defined for I, 2 C1-C6 alkyl-. In the embodiment, ring D is a saturated 6- to 7-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, hetAr is substituted with a pyridine ring. 2 has 1-2 ring nitrogens In one embodiment, hetAr is a 5- to 6-membered heterocyclic ring having a nitrogen atom. 2 Ha, Hello C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and C1-C 6 alkoxy (optionally substituted with 1 to 3 fluoro) In one embodiment, hetAr is optionally substituted with one or more substituents selected from the group consisting of: 2 teeth, A 6-membered heteroaryl ring having 1-2 ring nitrogen atoms and halogen, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and C1-C6 alkoxy (1 one or more substituents independently selected from the group consisting of: Non-limiting examples include the following structures: [ka] [ka]

[0161] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is a hetAr 2 (C1-C6 alkyl)C(=O )-, wherein the alkyl moiety is OH, hydroxyC1-C6 alkyl, or C1 -C6 alkoxy optionally substituted, hetAr 2 is as defined for Formula I Ori, hetAr 2 (C1-C6 alkyl)C(=O)-. In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. and ring D is unsubstituted. 2 (C1-C6 alkyl The alkyl portion of hetA(=O)- is unsubstituted. r 2 is a 5- to 6-membered heterocyclic ring having 1 to 2 ring nitrogen atoms. , hetAr 2 is optionally substituted with halogen, C1-C6 alkyl (1 to 3 fluoro). and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). In one embodiment, the alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: ite, hetAr 2 is a six-membered ring having one or two ring nitrogen atoms and one or more halogen atoms. Non-limiting examples include the following structures: [ka]

[0162] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is a hetAr 2 C(=O)- and hetA r 2 is as defined for Formula I, 2 C(=O)-. In embodiments, ring D is a saturated 6- to 7-membered heterocyclic ring having two ring nitrogen atoms, D is unsubstituted. In one embodiment, ring D is a saturated ring having two ring nitrogen atoms. In one embodiment, hetAr is a 7-membered heterocyclic ring, and Ring D is unsubstituted. 2 is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. etAr 2 is optionally substituted with halogen, C1-C6 alkyl (1 to 3 fluoro) ), and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro) In one embodiment, the aryl group is optionally substituted with one or more substituents independently selected from , hetAr 2 is a 6-membered ring having 1-2 ring nitrogen atoms, and C1-C6 alkoxy Non-limiting examples include the following structures: [ka]

[0163] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is a hetAr 1 C(=O)- and hetCy c 1 is as defined for formula I. In one embodiment, ring D is a ring In one embodiment, ring D is a substituted, saturated 6-membered heterocyclic ring having a nitrogen atom. In one embodiment, hetCyc 1 is a 4- to 6-membered saturated complex having a ring nitrogen atom and the heterocyclic ring is optionally substituted with C1-C6 alkoxy substituents. Non-limiting examples include the following structures: [ka]

[0164] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is hetCyc 1 C1-C6 alkyl-, hetCyc 1is as defined for formula I. In one embodiment, ring D is , a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is It is unsubstituted. In one embodiment, hetCyc 1 is a ring oxygen atom-containing In one embodiment, hetCyc is a 3-membered saturated heterocyclic ring. 1 is not replaced Non-limiting examples include the following structures: [ka]

[0165] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with oxo groups, and E is R 3 R 4 NC(=O)- and R 3 and R 4 is as defined for formula I. In one embodiment, ring D is a ring having two ring nitrogens. In one embodiment, ring D is a saturated 6-membered heterocyclic ring having a substituted or unsubstituted aryl group. Non-limiting examples include the following structures: [ka]

[0166] In one embodiment, ring D is a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms. and ring D is (a) a C1-C3 alkyl group optionally substituted with halogen, OH, or 1 to 3 fluoro groups. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is a hetAr 2 and hetAr 2 is expressed in Eq. In one embodiment, ring D has two ring nitrogen atoms. and ring D is unsubstituted. Ar 2 is a 5- to 6-membered heterocyclic ring having 1 to 2 ring nitrogen atoms. Te, hetAr 2 is halogen, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). In one embodiment, the alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: Hey, hetAr 2 is a six-membered ring having one or two ring nitrogen atoms, and and optionally substituted with koxy. Non-limiting examples include the following structures: [ka]

[0167] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 8-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group As used herein, the term "two rings" refers to a ring in which ring D is a saturated 7- or 8-membered bridged heterocycle. The phrase "having a ring nitrogen atom of" means that the ring nitrogen atom is one of the two ring nitrogen atoms shown in ring D of formula I. is a nitrogen atom, and one of the ring nitrogen atoms is X 1 , X 2 , X 3 , and X 4 to form a ring containing The other ring nitrogen atom is bonded to the E group shown in formula I. D has two nitrogen atoms and, optionally, a third ring heteroatom which is oxygen; Non-limiting examples of when the ring is a bridged heterocyclic ring include the following structures: [ka]

[0168] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group. Ring D is unsubstituted.

[0169] Ring D is a saturated 7- to 1-hydroxybenzoate having 2 to 3 ring heteroatoms independently selected from N and O. In one embodiment, when a 9-membered bridged heterocyclic ring, the ring D and E moieties of formula I are: minutes, [ka]

[0170] It can be represented by the non-limiting structure: [ka]

[0171] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group. Ring D is unsubstituted.

[0172] In one embodiment, Ring D has two ring nitrogen atoms represented by the following structure: is a saturated 7-membered bridged heterocyclic ring, [ka]

[0173] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group. Ring D is unsubstituted.

[0174] In one embodiment, Ring D has two ring nitrogen atoms and, optionally, a third ring nitrogen atom which is oxygen. and ring D is a saturated 7- to 8-membered bridged heterocyclic ring having a ring heteroatom of the formula: OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 to 4 groups independently selected from C1-C3 alkoxy optionally substituted with fluoro (b) a C3-C6 cycloalkylidene ring, or (c) optionally substituted with an oxo group; and E is as defined for formula I. In one embodiment, ring D is selected from the group consisting of two In one embodiment, ring D is a saturated 6- to 7-membered bridged heterocyclic ring having a ring nitrogen atom. Not replaced.

[0175] In one embodiment, Ring D has two ring nitrogen atoms and, optionally, a third ring nitrogen atom which is oxygen. and the ring D is a saturated 7- to 9-membered bridged heterocyclic ring having a ring heteroatom of the formula (a) halogen. C1-C3 alkyl optionally substituted with 1-3 fluoro, OH, or 1 to 4 independently selected from C1-C3 alkoxy optionally substituted with fluoro (b) a C3-C6 cycloalkylidene ring; or (c) an oxo group; and E is (a) hydrogen, (b) C1-C6 alkyl, (c) (C1-C6 alkoxy ) C1-C6 alkyl-, (d) (C1-C6 alkyl)C(=O)-, (e) (hydrogen (C2-C6) alkoxy)C(=O)-, (f) (C1-C6 alkoxy)C(=O) -, (g) (C3-C6 cycloalkyl)C(=O)-, (h) Ar 1 C1-C6 alkyl Ru-, (i) Ar 1(C1-C6 alkyl)C(=O)-, wherein the alkyl moiety , optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy Ar 1 (C1-C6 alkyl)C(=O)-, (j)hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro , hetAr 2 C1-C6 alkyl-, (K)hetAr 2 (C1-C6 alkyl)C( ═O)—, wherein the alkyl moiety is OH, hydroxyC1-C6 alkyl-, or is optionally substituted with C1-C6 alkoxy, hetAr 2 (C1-C6 alkyl) C(=O)-, (l)hetAr 2 C(=O)-, (m)hetCyc 1 C(=O)-, (o)R 3 R 4 NC(=O)-, (p)Ar 1 R 3 NC(=O)-, (q)hetAr 2 N(R 3 )C(=O)-, (r)(C1-C6 alkyl)SO2-, (t)hetAr 2 SO2-, (u) N-(C1-C6 alkyl)pyridinonyl, (v) Ar 1 C(=O)- , (w)Ar 1 OC(=O)-, (x)(C3-C6 cycloalkyl)CH2C(=O) -, (y) (C3-C6 cycloalkyl) (C1-C6 alkyl)SO2-, (z) Ar 1 (C1-C6 alkyl)SO2-, (aa)hetCyc 1 -OC(=O)-, (BB )hetCyc 1 -CH2-C(=O)-, and (cc)hetAr2 , or the group consisting of are selected from Ar 1 , hetAr 2 , R 3 , and hetCyc 1 is defined for formula I In one embodiment, ring D is selected from the following structures: [ka]

[0176] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The Talisker indicates the point of attachment to E.

[0177] In one embodiment, Ring D has two ring nitrogen atoms represented by the following structure: a saturated 7-8 membered bridged heterocyclic ring, [ka]

[0178] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The X in ring D indicates the point of attachment to E. 1 , X 2 , X 3 and X 4 The attachment point to the ring containing where E is (a) hydrogen, (b) C1-C6 alkyl, or (c) (C1-C6 alkoxy). C1-C6 alkyl-, (d) (C1-C6 alkyl)C(=O)-, (e) (hydroxy (C2-C6 alkyl)C(=O)-, (f) (C1-C6 alkoxy)C(=O)- (g) (C3-C6 cycloalkyl)C(=O)-, (h) Ar1 C1-C6 alkyl -, (i) Ar 1 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is optionally substituted with OH, hydroxyC1-C6 alkyl, or C1-C6 alkoxy There, Ar 1 (C1-C6 alkyl)C(=O)-, (j)hetAr 2 C1-C6 Al alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro; etAr 2 C1-C6 alkyl-, (k)hetAr 2 (C1-C6 alkyl)C(=O )-, wherein the alkyl moiety is OH, hydroxyC1-C6 alkyl-, or C optionally substituted with 1-C6 alkoxy, hetAr 2 (C1-C6 alkyl)C( =O)-, (l)hetAr 2 C(=O)-, (m)hetCyc 1 C(=O)-, (o )R 3 R 4 NC(=O)-, (p)Ar 1 N(R 3 )C(=(O)-, (q)hetAr 2 N(R 3 )C(=O)-, (r)(C1-C6 alkyl)SO2-, (t)hetAr 2 SO2-, (u) N-(C1-C6 alkyl)pyridinonyl, (v) Ar 1 C(=O) -, (w)Ar 1 OC(=O)-, (x)(C3-C6 cycloalkyl)CH2C(=O )-, (y) (C3-C6 cycloalkyl) (C1-C6 alkyl)SO2-, (z) A r 1 (C1-C6 alkyl)SO2-, (aa)hetCyc 1 -OC(=O)-, (b b) hetCyc 1 -CH2-C(=O)-, and (cc)hetAr 2 , the group consisting of wherein Ar 1 , hetAr 2 , R 3 , and hetCyc 1 Regarding formula I In one embodiment, ring D is unsubstituted.

[0179] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 8-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group and E is H. In one embodiment, ring D has two ring nitrogen atoms In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring. Represented, [ka]

[0180] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0181] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group wherein E is C1-C6 alkyl optionally substituted with 1 to 3 fluoro. In one embodiment, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure: [ka]

[0182] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0183] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group and E is (C1-C6 alkoxy)C optionally substituted with 1 to 3 fluoro. In one embodiment, ring D is a 1-C alkyl-alkyl group. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having the following structure: is expressed as [ka]

[0184] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0185] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being (a) C1-C3 alkyl optionally substituted with halogen, OH, 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 1 to 3 fluoro (b) a C3-C6 cycloalkylidene ring; or (c) an oxo group; E is (C1-C6 alkyl)C(=O)-, and the alkyl moiety Minutes, 1 to 3 fluoro or R g R h N-substituent (wherein R g and Rh is independent and optionally substituted with H or C1-C6 alkyl, In one embodiment, ring D is a saturated alkyl group having two ring nitrogen atoms. In one embodiment, ring D is a 7-8 membered bridged heterocyclic ring. And, [ka]

[0186] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0187] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is optionally substituted with 1 to 3 fluoro (hydroxy C2-C6 alkyl). In one embodiment, ring D is a saturated alkyl group having two ring nitrogen atoms. In one embodiment, ring D is a 7-8 membered bridged heterocyclic ring. And, [ka]

[0188] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0189] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group and E is (C1-C6 alkoxy)C(=O)-. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. wherein ring D is represented by the following structure: [ka]

[0190] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0191] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is C3-C6 cycloalkyl)C(=O)-, and the cycloalkyl The group includes C1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy). Optionally substituted with one or more substituents independently selected from C1-C6 alkyl- or the cycloalkyl is 1 to 3 rings independently selected from N and O. In one embodiment, the aryl group is substituted with a 5- to 6-membered heteroaryl ring having a heteroatom. E is C3-C6 cycloalkyl)C(=O)-, wherein the cycloalkyl is C1 -C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)C1- C6 alkyl-, optionally substituted with one or more substituents independently selected from C3 In one embodiment, ring D is a cycloalkyl group having two ring nitrogen atoms. In one embodiment, ring D is a saturated 7- to 8-membered bridged heterocyclic ring having a nitrogen atom. is represented by the structure [ka]

[0192] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0193] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is Ar 1 C1-C6 alkyl-, Ar 1 is defined for formula I As stated, Ar 1 In one embodiment, E is Ar 1 C1-C6 alkyl-, Ar 1 is halogen, C1-C6 alkyl (1- C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), (R p R q N) C1-C6 alkoxy-(wherein R p and R q German H or C1-C6 alkyl), and (hetAr a )C1-C6A Aryl-(wherein a is a 5- to 6-membered heteroaryl having 1 or 2 ring nitrogen atoms. a cyclic ring, optionally substituted with one or more substituents independently selected from the group consisting of phenyl, Ar 1 In one embodiment, ring D is 2 In one embodiment, ring D is a saturated 7- to 8-membered bridged heterocyclic ring having 1 or 2 ring nitrogen atoms. is represented by the following structure: [ka]

[0194] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0195] In one embodiment, Ring D has two ring nitrogen atoms and, optionally, a third ring nitrogen atom which is oxygen. and the ring is a saturated 7- to 9-membered bridged heterocyclic ring having a ring heteroatom of the formula: , OH, C1-C3 alkyl optionally substituted with 1 to 3 fluoro, or 1 to 4 independently selected from C1-C3 alkoxy optionally substituted with fluoro (b) a C3-C6 cycloalkylidene ring; or (c) an oxo group; and E is Ar 1(C1-C6 alkyl)C(=O)-, wherein the alkyl moiety , OH, hydroxy C1-C6 alkyl, C1-C6 alkoxy, R m R n N-, or R m R n optionally substituted with N-CH2-, wherein each R m and R n are independent, H or C1-C6 alkyl, and Ar 1 is as defined for formula I, A r 1 (C1-C6 alkyl)C(=O)-. In one embodiment, Ar 1 is replaced In one embodiment, the phenyl group is phenyl, which is unsubstituted or substituted with one or more halogens. and Ring D is a saturated 7- to 8-membered bridged heterocyclic ring having two ring nitrogen atoms. wherein ring D is represented by the following structure: [ka]

[0196] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0197] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group and E is hetAr 2 C1-C6 alkyl-, wherein the alkyl moiety is optionally substituted with 1 to 3 fluoro groups, hetAr 2 is as defined for Formula I , hetAr 2 In one embodiment, hetAr is C1-C6 alkyl-. 2 is a 5- to 6-membered ring heteroatom having 1 to 3 ring heteroatoms independently selected from N, O, and S. Heteroaryl ring or 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms Ar 2 is halogen, CN, C1-C6 alkyl (1-3 fluorine C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro) ), OH, C3-C6 cycloalkyl, and R e R f N-(wherein, R e and R f teeth independently, H or C1-C6 alkyl), In one embodiment, Ring D is optionally substituted with two ring nitrogen atoms. In one embodiment, ring D is a saturated 7- to 8-membered bridged heterocyclic ring having the following structure: It is represented by the structure, [ka]

[0198] In the formula, the wavy line represents X 1 , X 2, X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka] [ka] [ka] [ka]

[0199] In one embodiment, Ring D has two ring nitrogen atoms and, optionally, a third ring nitrogen atom which is oxygen. and the ring is a saturated 7- to 9-membered bridged heterocyclic ring having a ring heteroatom of the formula: , OH, C1-C3 alkyl optionally substituted with 1 to 3 fluoro, or 1 to 4 independently selected from C1-C3 alkoxy optionally substituted with fluoro (b) a C3-C6 cycloalkylidene ring; or (c) an oxo group; and E is hetAr 2 (C1-C6 alkyl)C(=O)-, The moiety is optionally substituted with OH, hydroxy C1-C6 alkyl, or C1-C6 alkoxy. Converted to hetAr 2 is as defined for Formula I, 2 (C1- C6 alkyl)C(=O)-. In one embodiment, the alkyl moiety is substituted In one embodiment, hetAr 2 is a 5- to 1-membered ring having 1 to 2 nitrogen atoms. A 6-membered heteroaryl ring is optionally substituted with one or more halogens. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is substituted by two ring nitrogens. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having the following ring atoms: Represented by the structure, [ka]

[0200] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example is the following structure: [ka]

[0201] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is Ar 1 C1-C6 alkyl-, where hetAr 2 Regarding formula I Ar 1 In one embodiment, hetAr 2is a 6-membered heteroaryl ring having 1 to 2 ring nitrogen atoms and halo aryl, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and (C1- C6 alkoxy)C1-C6 alkoxy-, one or more independently selected from the group consisting of In one embodiment, ring D is represented by the structure: And, [ka]

[0202] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka] [ka] [ka]

[0203] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 8-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is hetCyc 1C(=O)-, hetCyc 1 Regarding formula I as defined in 1 In one embodiment, the formula is C(=O)-. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. wherein ring D is represented by the following structure: [ka]

[0204] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0205] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is R 3 R 4 NC(=O)-, and R 3 is H or C1-C6 Al Kill and R 4 is C1-C6 alkyl, R 3 R 4 NC(=O)-. In embodiments, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure: [ka]

[0206] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0207] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is Ar 1 N(R 3 )C(=O)-, and Ar 1 and R 3 is represented by formula I Ar 1 N(R 3 )C(=O)-. In one embodiment Hey, Ar 1 is unsubstituted or C1-C6 alkoxy (1 to 3 full In one embodiment, ring D is substituted with In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure: [ka]

[0208] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0209] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group and E is hetAr 2 N(R 3 )C(=O)- and hetAr 2 and R 3 is as defined for Formula I. In one embodiment, 2 is placed unsubstituted or C1-C6 alkoxy (optionally substituted with 1-3 fluoro In one embodiment, ring D is a saturated 7-membered ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the structure: , [ka]

[0210] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example is the following structure: [ka]

[0211] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is (C1-C6 alkyl)SO2-, and the alkyl portion is 1 to 3 Optionally, the alkyl group is (C-C alkyl)SO-, optionally substituted with one fluoro. In the embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is Represented by the structure, [ka]

[0212] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0213] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group and E is hetAr 2 SO2- and hetAr 2 is defined for Formula I In one embodiment, hetAr 2 is not substituted or Substituted with C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). In an embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure: [ka]

[0214] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example is the following structure: [ka]

[0215] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group and E is N-(C1-C6 alkyl)pyridinonyl. and Ring D is a saturated 7- to 8-membered bridged heterocyclic ring having two ring nitrogen atoms. wherein ring D is represented by the following structure: [ka]

[0216] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0217] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is Ar 1 C(=O)- and Ar 1 is defined for Formula I In one embodiment, Ar 1 is halogen, C1-C6 alkyl (1 to 3 fluoro), and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). optionally substituted with one or more substituents independently selected from the group consisting of or Ar 1 is a 5- to 6-membered heterocyclic ring having two ring nitrogen atoms In one embodiment, ring D is a phenyl ring fused to In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having the following structure: It is expressed as [ka]

[0218] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0219] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is Ar 1 OC(=O)- and Ar 1 is defined for Formula I In one embodiment, Ar 1 is unsubstituted. , Ring D is unsubstituted. In one embodiment, Ring D has two ring nitrogen atoms In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring. Represented, [ka]

[0220] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talirisk indicates the point of attachment to E. Non-limiting examples include the following structures: [ka]

[0221] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is C3-C6 cycloalkyl)CH2C(=O)-, and alkyl The moiety is optionally substituted with 1-3 fluoro 2C(=O)-. In one embodiment, ring D is a saturated 7-membered ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the structure: , [ka]

[0222] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0223] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is (C3-C6 cycloalkyl)(C1-C3 alkyl)SO2- The alkyl moiety is optionally substituted with 1 to 3 fluoro groups (C3-C6 cycloalkyl). In one embodiment, ring D is 2 In one embodiment, ring D is a saturated 7- to 8-membered bridged heterocyclic ring having 1 or 2 ring nitrogen atoms. is represented by the following structure: [ka]

[0224] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0225] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is Ar 1 (C1-C6 alkyl)SO2-, and Ar 1 Regarding formula I In one embodiment, Ar 1 is not replaced. In embodiments, Ring D is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure: [ka]

[0226] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0227] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is hetCyc 1 -OC(=O)-, hetCyc 1 is represented by formula I In one embodiment, ring D has two ring nitrogen atoms. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having the following structure: It is expressed as [ka]

[0228] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0229] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, and the ring is halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or 1 independently selected from C1-C3 alkoxy optionally substituted with 3 fluoro Optionally substituted with four groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group E is hetCyc 1 -CH2-C(=O)-, hetCyc 1 teeth, As defined for formula I. In one embodiment, ring D is a ring having two nitrogen atoms. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having the structure: is represented by [ka]

[0230] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0231] In one embodiment of Formula I, ring D has two ring nitrogen atoms and, optionally, oxygen. and a third ring heteroatom, the ring being (a) halogen, OH, 1 to 3 fluoro. optionally substituted C1-C3 alkyl or optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2- in Yes, hetAr 2 is as defined for formula I. In one embodiment, h etAr 2 is a 6-membered ring having 1 to 2 ring nitrogen atoms, and is C1-C6 alkoxy In one embodiment, ring D is a saturated ring having two ring nitrogen atoms. In one embodiment, ring D is a 7-8 membered bridged heterocyclic ring. R, [ka]

[0232] In the formula, the wavy line represents X 1 , X 2 , X3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0233] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group. The phrase "having two ring nitrogen atoms" when referring to an 11-membered bridged heterospirocyclic ring is The ring nitrogen atoms are the two ring nitrogen atoms shown in ring D of formula I, and one of the ring nitrogen atoms X 1 , X 2 , X 3 , and X 4 and the other ring nitrogen atom is bonded to a ring containing formula I The ring D is a saturated 7-membered ring having two nitrogen atoms. Non-limiting examples of 11-membered bridged heterospirocyclic rings include the following structures: [ka] [ka]

[0234] In the formula, the wavy line represents X 1 , X 2 , X3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E, and each of the rings is selected from the group consisting of (a) halogen, OH, 1 to 3 C1-C3 alkyl optionally substituted with fluoro or optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from substituted C1-C3 alkoxy; 6 cycloalkylidene ring, or (c) optionally substituted with an oxo group. In the formula, ring D is unsubstituted.

[0235] When ring D is a saturated 7- to 11-membered heterospirocyclic ring having two ring nitrogen atoms, In embodiments, the ring D and E moieties of formula I are: [ka]

[0236] It can be represented by the non-limiting structure: [ka]

[0237] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing Each of the rings is (a) a C1-C3 optionally substituted with halogen, OH, or 1 to 3 fluoro. alkyl, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring; or (c) and optionally substituted with an oxo group, and E is as defined for formula I. In this embodiment, ring D is unsubstituted.

[0238] In one embodiment, ring D is represented by the following structure: [ka]

[0239] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E, and (a) halogen, OH, 1-3 fluoro are optional. Substituted C1-C3 alkyl or C1- optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C3 alkoxy, In one embodiment, the ring D is optionally substituted with an oxo group. is not substituted.

[0240] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is (a) hydrogen, (b) 1 to 3 fluorines. (d) (C1-C6 alkyl)C(=O )-, wherein the alkyl moiety is 1 to 3 fluoro or R g R h N-substituent ( In the formula, R g and R h are independently H or C1-C6 alkyl (C1-C6 alkyl)C(=O)-, (f) (C1-C6 alkoxy)C (=O)-, (l)hetAr 2 C(=O)-, (o)R 3 R 4 NC(=O)-, (s) Ar 1 SO2-, (t)hetAr 2 SO2-, (v) Ar 1 C(=O)-, (cc)h etAr 2 and (dd) C-C cycloalkyl; tAr 2 , Ar 1 , R 3 , and R 4 is as defined for Formula I. In this embodiment, the ring D is unsubstituted.

[0241] In one embodiment, Ring D has two ring nitrogen atoms represented by the following structure: is a saturated 9-membered bridged heterocyclic ring, [ka]

[0242] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E, and the ring is (a) halogen, OH, 1 to 3 fluorines, C1-C3 alkyl optionally substituted with 1 to 3 fluoro; (b) 1 to 4 groups independently selected from C1-C3 alkoxy, or (c) an oxo group; and E is (a) hydrogen, (d) (C1-C6 alkoxy)C(=O)-, and (o) R 3 R 4NC(=O)-, In one embodiment, Ring D is unsubstituted.

[0243] In one embodiment, ring D is a saturated 7-membered ring having two ring nitrogen atoms. 1 to 11-membered heterospirocyclic ring, the ring being selected from the group consisting of (a) halogen, OH, 1 to 3 fullerenes, C1-C3 alkyl optionally substituted with fluoro or optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy, a chloroalkylidene ring, or (c) optionally substituted with an oxo group, and E is hydrogen. In one embodiment, the ring D is represented by the following structure: [ka]

[0244] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tri-risk indicates the point of attachment to E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0245] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with oxo groups, and E is (b) 1 to 3 fluoro groups optionally In one embodiment, the ring D is a C1-C3 alkyl substituted with the following structure: is represented by [ka]

[0246] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tri-risk indicates the point of attachment to E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0247] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is (C1-C6 alkyl)C(=O )-, wherein the alkyl portion is 1 to 3 fluoro or R g R h N-(wherein, R g and R h are independently H or C1-C6 alkyl In one embodiment, the ring D is (C1-C6 alkyl)C(=O)-. It is represented by the structure below, [ka]

[0248] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tri-risk indicates the point of attachment to E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0249] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is (C1-C6 alkoxy)C(= In one embodiment, the ring D is represented by the following structure: [ka]

[0250] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tri-risk indicates the point of attachment to E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0251] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is hetAr 2 C(=O)- , hetAr 2 is as defined for formula I. In one embodiment, het Ar 2 is a 5- to 6-membered heterocyclic ring having 1 to 2 ring nitrogen atoms. Te, hetAr 2 is halogen, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). In one embodiment, the alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: Hey, hetAr 2 is a 6-membered ring having 1 to 2 ring nitrogen atoms and C1-C6 Optionally substituted with alkoxy. In one embodiment, Ring D is unsubstituted. In one embodiment, ring D is represented by the following structure: [ka]

[0252] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talirisk indicates the point of attachment to E. Non-limiting examples include the following structures: [ka]

[0253] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is R 3 R 4 NC(=O)-, R 3 and R 4 is as defined for formula I. In one embodiment, R 3 teeth H and R 4 is C1-C6 alkyl. In one embodiment, the ring D is Represented by the structure, [ka]

[0254] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tri-risk indicates the point of attachment to E. In one embodiment, the ring D is unsubstituted. Non-limiting examples include the following structures: [ka]

[0255] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is Ar 1 SO2- and Ar 1 teeth , as defined for formula I. In one embodiment, Ar 1 is a halogen, C 1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and C1-C6 alkoxy one independently selected from the group consisting of alkoxy (optionally substituted with 1 to 3 fluoro) In one embodiment, Ring D is phenyl optionally substituted with the above substituents. In one embodiment, the ring D is represented by the following structure: [ka]

[0256] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talirisk indicates the point of attachment to E. Non-limiting examples include the following structures: [ka]

[0257] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is hetAr 2 SO2- and h etAr 2 is as defined for Formula I. In one embodiment, 2 is a 5-6 membered heterocyclic ring having 1-2 ring nitrogen atoms. hetAr 2 is optionally substituted with halogen, C1-C6 alkyl (1 to 3 fluoro) and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). Optionally substituted with one or more substituents independently selected from the group: Te, hetAr 2 is a 6-membered ring having 1-2 ring nitrogen atoms and is a C1-C6 alkyl In one embodiment, Ring D is optionally substituted with koxy. In one embodiment, the ring D is represented by the following structure: [ka]

[0258] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talirisk indicates the point of attachment to E. Non-limiting examples include the following structures: [ka]

[0259] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is Ar 1 C(=O)- and Ar 1 is as defined for formula I. In one embodiment, Ar 1 is a halogen , C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and C1-C6 alkyl independently selected from the group consisting of alkoxy (optionally substituted with 1 to 3 fluoro) In one embodiment, ring D is phenyl optionally substituted with one or more substituents. , unsubstituted. In one embodiment, the ring D is represented by the following structure: [ka]

[0260] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talirisk indicates the point of attachment to E. Non-limiting examples include the following structures: [ka]

[0261] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is hetAr 2 and hetAr 2 is as defined for Formula I. In one embodiment, 2 is 1 HetA is a 5-6 membered heterocyclic ring having 2 to 5 ring nitrogen atoms. r 2 is selected from halogen, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). In one embodiment, the tAr 2 is a 6-membered ring having 1 to 2 ring nitrogen atoms and is C1-C6 alkoxy Optionally substituted. In one embodiment, the ring D is unsubstituted. In this embodiment, the ring D is represented by the following structure: [ka]

[0262] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talirisk indicates the point of attachment to E. Non-limiting examples include the following structures: [ka]

[0263] In one embodiment, ring D is a saturated 7-11 membered heterospiro ring having two ring nitrogen atoms. a cyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from koxy; (c) a C3-C6 cycloalkylidene ring; or (c) optionally substituted with an oxo group, and E is C3-C6 cycloalkyl In one embodiment, the ring D is unsubstituted. is represented by the following structure: [ka]

[0264] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talirisk indicates the point of attachment to E. Non-limiting examples include the following structures: [ka]

[0265] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused ring complex having two ring nitrogen atoms. a heterocyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl optionally substituted with 1 to 3 fluoro; (b) 1 to 4 groups independently selected from alkoxy; and (c) a C3-C6 cycloalkylidene ring. or (c) optionally substituted with an oxo group. The phrase "having two ring nitrogen atoms" when referring to a 10-membered bicyclic fused heterocyclic ring is The ring nitrogen atoms are the two ring nitrogen atoms shown in ring D of formula I, and one of the ring nitrogen atoms X 1 , X 2 , X 3 , and X 4 and the other ring nitrogen atom is bonded to a ring containing formula I The fused rings include 5,5, 5,6, 6,5, and 6,6 fused ring systems. In one embodiment, the ring D is represented by the following structure: It is expressed as [ka]

[0266] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E, and the ring is (a) halogen, OH, 1 to 3 fluorines, C1-C3 alkyl optionally substituted with 1 to 3 fluoro; (b) 1 to 4 groups independently selected from C1-C3 alkoxy, or (c) an oxo group. , wherein ring D is unsubstituted.

[0267] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused ring complex having two ring nitrogen atoms. a heterocyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl optionally substituted with 1 to 3 fluoro; (b) 1 to 4 groups independently selected from alkoxy; and (c) a C3-C6 cycloalkylidene ring. or (c) optionally substituted with an oxo group, and E is as defined for formula I is.

[0268] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused ring complex having two ring nitrogen atoms. a heterocyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl optionally substituted with 1 to 3 fluoro; (b) 1 to 4 groups independently selected from alkoxy; and (c) a C3-C6 cycloalkylidene ring. or (c) optionally substituted with an oxo group, and E is hydrogen or (C1-C6 alkoxy). In one embodiment, ring D is represented by the following structure: [ka]

[0269] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tririsk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted.

[0270] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused ring complex having two ring nitrogen atoms. a heterocyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl optionally substituted with 1 to 3 fluoro; (b) 1 to 4 groups independently selected from alkoxy; and (c) a C3-C6 cycloalkylidene ring. or (c) optionally substituted with an oxo group, and E is hydrogen. and ring D is represented by the following structure: [ka]

[0271] In the formula, the wavy line represents X1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E. In one embodiment, ring D is unsubstituted. A non-limiting example is the following structure: [ka]

[0272] In one embodiment, Ring D is a saturated 9-10 membered bicyclic fused ring complex having two ring nitrogen atoms. a heterocyclic ring, the ring being (a) optionally substituted with halogen, OH, or 1 to 3 fluoro; C1-C3 alkyl optionally substituted with 1 to 3 fluoro; (b) 1 to 4 groups independently selected from alkoxy; and (c) a C3-C6 cycloalkylidene ring. or (c) optionally substituted with an oxo group, and E is (C1-C6 alkoxy)C( In one embodiment, ring D is represented by the following structure: [ka]

[0273] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tri-risk indicates the point of attachment to E. In one embodiment, the ring D is unsubstituted. A non-limiting example is the following structure: [ka]

[0274] In one embodiment, Formula I includes compounds of Formula IA, wherein:

[0275] X 1 , X 2 , X 3 , and X 4 are independently CH, CF, or N, and X 1 , X 2 , X 3 , and X 4 0, 1, or 2 of are N,

[0276] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN, or -CH(CN)CH3,

[0277] B,

[0278] (a) hydrogen,

[0279] (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro;

[0280] (c) hydroxy C2-C6 alkyl-, wherein the alkyl moiety is 1 to 3 fluoro or a hydroxy C2-C optionally substituted with a C3-C6 cycloalkylidene ring. 6 alkyl-,

[0281] (d) dihydroxyC3-C6 alkyl-, wherein the alkyl moiety is C3-C6 cyclo dihydroxyC3-C6 alkyl-, optionally substituted on the alkylidene ring;

[0282] (e) (C1-C6 alkoxy)C1-C6 alkoxy optionally substituted with 1 to 3 fluoro groups kill-,

[0283] (f)(R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with OH. Converted to R 1 and R 2are independently H or C1-C6 alkyl (1 to 3 fluoro (R 1 R 2 N) C1-C6 alkyl-,

[0284] (g)hetAr 1 C1-C3 alkyl-, where hetAr 1 But N, O, and S and a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from and optionally substituted with one or more independently selected C1-C6 alkyl substituents; hetAr 1 C1-C3 alkyl-,

[0285] (h) (C3-C6 cycloalkyl)C1-C3 alkyl-, wherein the cycloalkyl (C3-C6 cycloalkyl)C1-C3 alkyl optionally substituted with OH -,

[0286] (i)(hetCyc a ) C1-C3 alkyl-,

[0287] (j)hetCyc a -,

[0288] (k) C3-C6 cycloalkyl-, wherein the cycloalkyl is optionally substituted with OH. C3-C6 cycloalkyl-,

[0289] (l) (C1-C4 alkyl)C(=O)O-C1-C6 alkyl-, where C1-C 4 alkyl moieties and C1-C6 alkyl moieties each optionally and independently have 1 to 3 (C1-C4 alkyl)C(=O)O-C1-C6 alkyl, substituted with fluoro Ru-, or

[0290] (m)(R1 R 2 N)C(=O)C1-C6 alkyl-, where R 1 and R 2 becomes independent and H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro). , (R 1 R 2 N)C(=O)C1-C6 alkyl-;

[0291] hetCyc a - has 1 to 2 ring heteroatoms independently selected from N and O 4-6 membered heterocyclic ring, optionally containing OH, C1-C6 alkyl (1-3 fluoro) substituted with), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C 6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl-, and optionally substituted with one or more substituents independently selected from the group consisting of fluoro, ... etCyc a is substituted with oxo,

[0292] Ring D is [ka]

[0293] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 The asterisk indicates the point of attachment to the ring containing the The ring A indicates the point of attachment to the E group, and the ring D is (a) any of halogen, OH, and 1 to 3 fluoro. optionally substituted C1-C3 alkyl or C optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from 1-C3 alkoxy; a chilidene ring, or (c) optionally substituted with an oxo group.

[0294] E is,

[0295] (a) hydrogen,

[0296] (c) (C1-C6 alkoxy)C1-C6 alkoxy optionally substituted with 1 to 3 fluoro groups kill-,

[0297] (d) (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is 1 to 3 Fluoro or R g R h N-substituent (wherein R g and R h are independently H or C (C1-C6 alkyl)C(=O) optionally substituted with (C1-C6 alkyl)C(=O) -,

[0298] (e) (hydroxyC2-C6 alkyl)C(= optionally substituted with 1 to 3 fluoro O)-,

[0299] (f) (C1-C6 alkoxy)C(=O)-,

[0300] (g) (C3-C6 cycloalkyl)C(=O)-, wherein the cycloalkyl is C 1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)C1 -C6 alkyl-, or Or the cycloalkyl may be a ring heteroatom selected from 1 to 3 ring heteroatoms independently selected from N and O. (C3-C6 cycloalkyl) substituted with a 5-6 membered heteroaryl ring having C(=O)-,

[0301] (h)Ar 1 C1-C6 alkyl-,

[0302] (i)Ar1 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is OH , hydroxy C1-C6 alkyl-, C1-C6 alkoxy, R m R n N- or R m R n N-CH2-(in the formula, each R m and R n are independently H or C1-C6 alkyl Optionally substituted with Ar 1 (C1-C6 alkyl)C(=O)-,

[0303] (j)hetAr 2 C1-C6 alkyl-, wherein the alkyl moiety is 1 to 3 fluorines. optionally substituted with Ar 2 C1-C6 alkyl-,

[0304] (k)hetAr 2 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety , optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy HetAr 2 (C1-C6 alkyl)C(=O)-,

[0305] (l)hetAr 2 C(=O)-,

[0306] (m)hetCyc 1 C(=O)-,

[0307] (n)hetCyc 1 C1-C6 alkyl-,

[0308] (o)R 3 R 4 NC(=O)-, or

[0309] (cc)hetAr 2 , and

[0310] Ar 1 is optionally substituted with halogen, CN, C1-C6 alkyl (1 to 3 fluoro) C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), R e R f N -(In the formula, R e and R f are independently H or C1-C6 alkyl), (R p R q N) C1-C6 alkoxy-(wherein R p and R q are independently H or C1-C6 alkyl), and (hetAr a ) C1-C6 alkyl-(wherein, a is a 5- to 6-membered heteroaryl ring having 1 to 2 ring nitrogen atoms) phenyl optionally substituted with one or more substituents selected from the group consisting of phenyl, ... 1 is a 5- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O a phenyl ring fused to a ring of the formula

[0311] hetAr 2 are independently 1 to 3 ring hetero atoms independently selected from N, O, and S. 5-6-membered heteroaryl ring having 1-3 nitrogen atoms, or 9-1 0-membered bicyclic heteroaryl ring, hetAr 2 But halogen, CN, C1-C6 alkane alkyl (optionally substituted with 1 to 3 fluoro), C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), (C1-C6 alkoxy)C1-C6 alkyl-(1-3 optionally substituted with fluoro) optionally substituted with fluoro, R e R f N-(wherein, R eand R f became independent, H or C1-C6 alkyl), OH, (C1-C6 alkoxy)C1-C6 alkoxy one or more independently selected from the group consisting of koxy-, and C3-C6 cycloalkyl and optionally substituted with a substituent of

[0312] hetCyc 1 is 1 to 2 ring heteroatoms independently selected from N, O, and S and the heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having the formula: and halogen;

[0313] R 4 is C1-C6 alkyl.

[0314] In one embodiment of formula IA, ring D is unsubstituted.

[0315] In one embodiment of formula IA, X 1 is N and X 2 , X 3 , and X 4 is CH be.

[0316] In one embodiment of formula IA, A is CN.

[0317] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH and A is CN.

[0318] In one embodiment of formula IA, B is C1- optionally substituted with 1 to 3 fluoro. It is a C6 alkyl.

[0319] In one embodiment of formula IA, B is optionally substituted with 1 to 3 fluoro (C1 -C6 alkoxy) C1-C6 alkyl, or hydroxy C2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. oxyC2-C6 alkyl-.

[0320] In one embodiment of formula IA, B is optionally substituted with 1 to 3 fluoro (C1 In one embodiment of formula IA, B is -C6 alkoxy)C1-C6 alkyl-. , (C1-C6 alkoxy)C2-C6 alkyl optionally substituted with 1 to 3 fluoro -It is.

[0321] In one embodiment of formula IA, B is hydroxyC2-C6 alkyl- the alkyl moiety is optionally substituted with a C3-C6 cycloalkylidene ring; 2-C6 alkyl-. In one embodiment, the alkyl moiety is unsubstituted.

[0322] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted (C1-C6 alkoxy)C1-C6 alkyl- or hydroxyC2-C6 Alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. It is a hydroxy C2-C6 alkyl-.

[0323] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. In one embodiment, the alkyl group is substituted (C1-C6 alkoxy)C1-C6 alkyl-. B is a (C1-C6 alkoxy)C2-C6 alkoxy optionally substituted with 1 to 3 fluoro groups. Kill-.

[0324] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is hydroxy C2-C6 alkyl -, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. , hydroxyC2-C6 alkyl-. In one embodiment, the alkyl portion of the B group is , not replaced.

[0325] In one embodiment of formula IA, E is Ar 1 C1-C6 alkyl-, hetAr 2 C 1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Iru, hetAr 2 C1-C6 alkyl-, or hetAr 2 C1-C6 alkyl- Yes, Ar 1 and hetAr 2 is as defined for formula IA.

[0326] In one embodiment of formula IA, E is Ar 1 C1-C6 alkyl-, hetAr 2 C 1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Iru, hetAr 2C1-C6 alkyl-, or Ar 1 (C1-C6 alkyl)C(= O)- and Ar 1 is unsubstituted phenyl, and hetAr 2 is a ring nitrogen atom A 5-6 membered heterocyclic ring having 1 to 3 carbon atoms and halogen, C1-C6 alkyl (1 to 3 carbon atoms) fluoro), and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). and optionally substituted with one or more substituents independently selected from the group consisting of In one embodiment of formula IA, hetAr 2 has 1 to 2 ring nitrogen atoms and a 6-membered heterocyclic ring, optionally containing halogen, C1-C6 alkyl (1 to 3 fluoro). C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro) and optionally substituted with one or more substituents independently selected from the group consisting of:

[0327] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted (C1-C6 alkoxy)C1-C6 alkyl- or hydroxyC2-C6 Alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. E is a hydroxy C2-C6 alkyl- 1 C1-C6 alkyl, hetAr 2 C1-C6 alkyl, wherein the alkyl portion is optionally 1 to 3 fluoro groups. is replaced by hetAr 2 C1-C6 alkyl, or Ar 1 (C1-C6 alkyl Ar 1 and hetAr 2 is defined for formula IA This is the case.

[0328] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted (C1-C6 alkoxy)C1-C6 alkyl-, and E is Ar 1 C1-C 6Alkyl-, hetAr 2 C1-C6 alkyl-, where the alkyl moiety is 1 to 3 optionally substituted with fluoro, hetAr 2 C1-C6 alkyl-, or Ar 1 (C1-C6 alkyl)C(=O)-, and Ar 1 and hetAr 2 is expressed in formula IA. As defined above.

[0329] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted (C1-C6 alkoxy)C1-C6 alkyl-, and E is Ar 1 C1-C 6 alkyl-, and Ar 1 is as defined for formula IA.

[0330] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted (C1-C6 alkoxy)C1-C6 alkyl-, and E is hetAr 2 C 1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Iru, hetAr 2 C1-C6 alkyl-, hetAr 2 is defined for formula IA As it is justified.

[0331] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted (C1-C6 alkoxy)C1-C6 alkyl-, or E is Ar 1 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is OH, hydroxy Ar optionally substituted with C1-C6 alkyl- or C1-C6 alkoxy; 1 (C1-C6 alkyl)C(=O)-, and Ar 1 is defined for formula IA This is the case.

[0332] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is hydroxy C2-C6 alkyl -, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. , hydroxyC2-C6 alkyl-, and E is Ar 1 C1-C6 alkyl-, het Ar 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. HetAr is being replaced 2 C1-C6 alkyl-, or Ar 1 (C1-C6 alkyl )C(=O)-, and Ar 1 and hetAr 2 is defined for formula IA In one embodiment, the alkyl portion of the B group is unsubstituted.

[0333] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; hydroxyC2-C6 alkyl-, and E is Ar 1 C1-C6 alkyl-, and A r 1 is as defined for formula IA. In one embodiment, the alkyl group of the B group The ru portion is unsubstituted.

[0334] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is hydroxy C2-C6 alkyl -, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. , hydroxyC2-C6 alkyl-, and E is hetAr 2C1-C6 alkyl- wherein the alkyl portion is optionally substituted with 1 to 3 fluoro; 2 C 1-C6 alkyl- and hetAr 2 is as defined for formula IA Aru, hetAr 2 In one embodiment, the alkyl of the B group is C1-C6 alkyl-. The moiety is unsubstituted.

[0335] In one embodiment of formula IA, ring D is unsubstituted and X 1 is N and X 2 , X 3 , and X 4 is CH, A is CN, and B is C3-C6 cycloalkylidene hydroxyC2-C6 alkyl-, optionally substituted on the ring, and E is Ar 1 (C 1-C6 alkyl)C(=O)-, wherein the alkyl moiety is OH, hydroxyC1 -C6 alkyl- or C1-C6 alkoxy optionally substituted, Ar 1 (C 1-C6 alkyl)C(=O)-, and Ar 1 is defined for formula IA It is, Ar 1 (C1-C6 alkyl)C(=O)-. In one embodiment, Ar 1 In one embodiment, B is hydroxy C2-C6 alkyl. alkyl-, wherein the alkyl portion is unsubstituted, hydroxyC2-C6 alkyl -It is.

[0336] In one embodiment of formula IA, ring D is unsubstituted and X 2 is N and X 1 , X 3 , and X4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted C1-C6 alkyl, optionally substituted with 1 to 3 fluoro (C1-C6 alkyl) Coxy)C1-C6 alkyl-, or (hetCyc a ) C1-C3 alkyl- , E is Ar 1 C1-C6 alkyl- or Ar 1 (C1-C6 alkyl)C(=O)- wherein the alkyl moiety is OH, hydroxyC1-C6 alkyl-, or C1-C 6 optionally substituted with alkoxy, Ar 1 C1-C6 alkyl- or Ar 1 (C1 -C6 alkyl)C(=O)-, and hetCyc a and Ar 1 Regarding formula IA, As defined above.

[0337] In one embodiment of formula IA, ring D is unsubstituted and X 2 is N and X 1 , X 3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted C1-C6 alkyl-, and E is Ar 1 (C1-C6 alkyl)C(=O) -, wherein the alkyl moiety is OH, hydroxyC1-C6 alkyl-, or C optionally substituted with 1-C6 alkoxy, Ar 1 (C1-C6 alkyl)C(=O) - and Ar 1 is as defined for formula IA.

[0338] In one embodiment of formula IA, ring D is unsubstituted and X 2 is N and X 1 , X 3 , and X 4 is CH, A is CN, and B is optionally substituted with 1 to 3 fluoro. substituted (C1-C6 alkoxy)C1-C6 alkyl-, and E is Ar 1 C1-C 6 alkyl-, and Ar 1 is as defined for formula IA.

[0339] In one embodiment of formula IA, ring D is unsubstituted and X 2 is N and X 1 , X 3 , and X 4 is CH, A is CN, and B is (hetCyc a )C1-C3 alkyl- and E is Ar 1 C1-C6 alkyl-, hetCyc a and A r 1 is as defined for formula IA.

[0340] In one embodiment, Formula I includes compounds of Formula IB, wherein:

[0341] X 1 , X 2 , X 3 , and X 4 are independently CH, CF, or N, and X 1 , X 2 , X 3 , and X 4 0, 1, or 2 of are N,

[0342] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN, or -CH(CN)CH3,

[0343] B,

[0344] (a) hydrogen,

[0345] (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro;

[0346] (c) hydroxy C2-C6 alkyl-, wherein the alkyl moiety is 1 to 3 fluoro or a hydroxy C2-C optionally substituted with a C3-C6 cycloalkylidene ring. 6 alkyl-,

[0347] (d) dihydroxyC3-C6 alkyl-, wherein the alkyl moiety is C3-C6 cyclo dihydroxyC3-C6 alkyl-, optionally substituted on the alkylidene ring;

[0348] (e) (C1-C6 alkoxy)C1-C6 alkoxy optionally substituted with 1 to 3 fluoro groups kill-,

[0349] (f)(R 1 R 2 N) C1-C6 alkyl-, wherein the alkyl portion is optionally OH. is replaced by R 1 and R 2 are independently H or C1-C6 alkyl (1 to 3 fluorines) (R 1 R 2 N) C1-C6 alkyl-,

[0350] (g)hetAr 1 C1-C3 alkyl-, where hetAr 1 But N, O, and S and a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from and optionally substituted with one or more independently selected C1-C6 alkyl substituents; hetAr 1 C1-C3 alkyl-,

[0351] (h) (C3-C6 cycloalkyl)C1-C3 alkyl-, wherein the cycloalkyl (C3-C6 cycloalkyl)C1-C3 alkyl optionally substituted with OH -,

[0352] (i)(hetCyc a ) C1-C3 alkyl-,

[0353] (j)hetCyc a -,

[0354] (k) C3-C6 cycloalkyl-, wherein the cycloalkyl is optionally substituted with OH. C3-C6 cycloalkyl-,

[0355] (l) (C1-C4 alkyl)C(=O)O-C1-C6 alkyl-, where C1-C 4 alkyl moieties and C1-C6 alkyl moieties each optionally and independently have 1 to 3 (C1-C4 alkyl)C(=O)O-C1-C6 alkyl, substituted with fluoro Ru-, or

[0356] (m)(R 1 R 2 N)C(=O)C1-C6 alkyl-, where R 1 and R 2 becomes independent and H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro). , (R 1 R 2 N)C(=O)C1-C6 alkyl-,

[0357] hetCyc a - has 1 to 2 ring heteroatoms independently selected from N and O 4-6 membered heterocyclic ring, optionally containing OH, C1-C6 alkyl (1-3 fluoro) substituted with), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C 6 alkyl)C(=O)-, (C1-C6 alkoxy)C1-C6 alkyl-, and optionally substituted with one or more substituents independently selected from the group consisting of fluoro, ... etCyc a is substituted with oxo,

[0358] Ring D is [ka]

[0359] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; optionally substituted with an alkylidene ring, or (c) an oxo group;

[0360] E is,

[0361] (a) hydrogen,

[0362] (b) C1-C6 alkyl,

[0363] (c) (C1-C6 alkoxy)C1-C6 alkyl-,

[0364] (d) (C1-C6 alkyl)C(=O)-,

[0365] (e) (hydroxy C2-C6 alkyl)C(=O)-,

[0366] (f) (C1-C6 alkoxy)C(=O)-,

[0367] (g) (C3-C6 cycloalkyl)C(=O)-,

[0368] (h)Ar 1 C1-C6 alkyl-,

[0369] (i)Ar 1 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is OH , hydroxy C1-C6 alkyl-, C1-C6 alkoxy, R m R n N- or R m R n N-CH2-(in the formula, each R m and R n are independently H or C1-C6 alkyl Optionally substituted with Ar 1 (C1-C6 alkyl)C(=O)-,

[0370] (j)hetAr 2 C1-C6 alkyl-, wherein the alkyl moiety is 1 to 3 fluorines. optionally substituted with Ar 2 C1-C6 alkyl-,

[0371] (k)hetAr 2 (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety , optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy HetAr 2 (C1-C6 alkyl)C(=O)-,

[0372] (l)hetAr 2 C(=O)-,

[0373] (m)hetCyc 1 C(=O)-,

[0374] (o)R 3 R 4 NC(=O)-,

[0375] (p)Ar 1 R 3 NC(=O)-,

[0376] (q)hetAr 2 N(R 3 )C(=O)-,

[0377] (r) (C1-C6 alkyl)SO2-, wherein the alkyl moiety is 1 to 3 full-chain alkyl groups. (C1-C6 alkyl)SO2-, optionally substituted with fluoro;

[0378] (t)hetAr 2 SO2-,

[0379] (u) N-(C1-C6 alkyl)pyridinonyl,

[0380] (v)Ar 1 C(=O)-,

[0381] (w)Ar 1 OC(=O)-,

[0382] (x) (C3-C6 cycloalkyl)CH2C(=O)-,

[0383] (y) (C3-C6 cycloalkyl)(C1-C6 alkyl)SO2-,

[0384] (z)Ar 1 (C1-C6 alkyl)SO2-,

[0385] (aa)hetCyc 1 -OC(=O)-,

[0386] (bb)hetCyc 1 -CH2-C(=O)-, or

[0387] (cc)hetAr2 , and

[0388] Ar 1 is optionally substituted with halogen, CN, C1-C6 alkyl (1 to 3 fluoro) C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), R e R f N -(In the formula, R e and R f are independently H or C1-C6 alkyl), (R p R q N) C1-C6 alkoxy-(wherein R p and R q are independently H or C1-C6 alkyl), and (hetAr a ) C1-C6 alkyl-(wherein, a is a 5- to 6-membered heteroaryl ring having 1 to 2 ring nitrogen atoms) phenyl optionally substituted with one or more substituents selected from the group consisting of phenyl, ... 1 is a 5- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O a phenyl ring fused to a ring of the formula

[0389] hetAr 2 are independently 1 to 3 ring hetero atoms independently selected from N, O, and S. 5-6-membered heteroaryl ring having 1-3 nitrogen atoms, or 9-1 0-membered bicyclic heteroaryl ring, hetAr 2 But halogen, CN, C1-C6 alkane alkyl (optionally substituted with 1 to 3 fluoro), C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), (C1-C6 alkoxy)C1-C6 alkyl-(1-3 optionally substituted with fluoro) optionally substituted with fluoro, R e Rf N-(wherein, R e and R f became independent, H or C1-C6 alkyl), OH, (C1-C6 alkoxy)C1-C6 alkoxy one or more independently selected from the group consisting of koxy-, and C3-C6 cycloalkyl and optionally substituted with a substituent of

[0390] hetCyc 1 is 1 to 2 ring heteroatoms independently selected from N, O, and S and the heterocyclic ring is a 4- to 6-membered saturated heterocyclic ring having the formula: and halogen;

[0391] R 3 is H or C1-C6 alkyl;

[0392] R 4 is C1-C6 alkyl.

[0393] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH be.

[0394] In one embodiment of formula IB, X 1 and X 3 is N and X 2 and X 4 is C It's H.

[0395] In one embodiment of formula IB, A is CN.

[0396] In one embodiment of formula IB, ring D is [ka] and

[0397] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; an alkylidene ring, or (c) optionally substituted with an oxo group;

[0398] In one embodiment of formula IB, ring D is [ka] and

[0399] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tri-risk indicates the point of attachment to E, and ring D is unsubstituted.

[0400] In one embodiment of formula IB, B is C1- optionally substituted with 1 to 3 fluoro. C6 alkyl, (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C6 alkyl, hydroxy C2-C6 alkyl, and the alkyl portion is C3-C6 hydroxy Hydroxy C2-C6 alkyl, hetA, optionally substituted with a chloroalkylidene ring r 1 C1-C3 alkyl-, or (hetCyc a ) C1-C3 alkyl-, and h etAr 1and hetCyc a is as defined for formula IB.

[0401] In one embodiment of formula IB, B is C1- optionally substituted with 1 to 3 fluoro. In one embodiment of formula IB, B is C1-C6 alkyl. .

[0402] In one embodiment of formula IB, B is optionally substituted with 1 to 3 fluoro (C1 -C6 alkoxy)C1-C6 alkyl-, or hydroxyC2-C6 alkyl- The alkyl moiety is optionally substituted with a C3-C6 cycloalkylidene ring. It is oxyC2-C6 alkyl-.

[0403] In one embodiment of formula IB, B is optionally substituted with 1 to 3 fluoro (C1 In one embodiment of formula IB, B is -C6 alkoxy)C1-C6 alkyl-. , (C1-C6 alkoxy)C2-C6 alkyl optionally substituted with 1 to 3 fluoro -It is.

[0404] In one embodiment of formula IB, B is hydroxyC2-C6 alkyl- the alkyl moiety is optionally substituted with a C3-C6 cycloalkylidene ring; In one embodiment, the alkyl portion of the B group is substituted. do not have.

[0405] In one embodiment of formula IB, B is hetAr 1 C1-C3 alkyl-, h etAr 1 is as defined for formula IB.

[0406] In one embodiment of formula IB, B is (hetCyc a ) C1-C3 alkyl- hetCyc a is as defined for formula IB.

[0407] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro. Formula I In one embodiment of -B, B is C1-C6 alkyl.

[0408] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C6 alkyl- or hydroxyC2-C6 alkyl-, wherein the alkyl moiety is C HydroxyC2-C6 alkyl optionally substituted with a 3-C6 cycloalkylidene ring In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH In one embodiment, X 1 and X 3 is N and X 2 and X4 is CH .

[0409] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro In one embodiment, X is C alkyl-. 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 teeth , CH.

[0410] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring In one embodiment, the alkyl portion of the B group is unsubstituted. , X 1 is N and X 2 , X 3 , and X 4is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0411] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hetAr 1 C1-C3 alkyl-, hetAr 1 is expressed in equation IB. In one embodiment, X 1 is N and X 2 , X 3 ,oh Call X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 Oh and X 4 is CH.

[0412] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (hetCyc a ) C1-C3 alkyl-, hetCyc a is the expression As defined for IB. In one embodiment, X 1is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N, X 2 and X 4 is CH.

[0413] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, and ring D teeth, [ka] and

[0414] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an alkylidene ring, or (d) an oxo group. In one embodiment, the ring D is unsubstituted. 1 is N and X 2 , X 3 , and X 4is CH. In one embodiment, X 1 and X 3 is N , X 2 and X 4 is CH.

[0415] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C6 alkyl- or hydroxyC2-C6 alkyl-, wherein the alkyl moiety is C HydroxyC2-C6 alkyl optionally substituted with a 3-C6 cycloalkylidene ring - and ring D is [ka] and

[0416] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an alkylidene ring, or (d) an oxo group. In one embodiment, the ring D is unsubstituted. 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N , X 2 and X 4 is CH.

[0417] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0418] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The valence risk indicates the point of attachment to E, and ring D is unsubstituted. 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 Oh and X 3 is N and X 2 and X 4 is CH.

[0419] In one embodiment of formula IB, X1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hetAr 1 C1-C3 alkyl-, hetAr 1 is expressed in equation IB. and ring D is as defined above. [ka] and

[0420] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an alkylidene ring, or (d) an oxo group. In one embodiment, ring D is unsubstituted. 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0421] In one embodiment of formula IB, X 1 is N and X2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hetAr 1 C1-C3 alkyl-, hetCyc a is the formula IB and ring D is as defined for [ka] and

[0422] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an alkylidene ring, or (d) an oxo group. In one embodiment, ring D is unsubstituted. 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0423] In one embodiment of formula IA, E is hetAr 2 C1-C6 alkyl- the alkyl portion is optionally substituted with 1 to 3 fluoro; 2 C1-C6 Alkyl-, hetAr 2 C(=O)-, Ar 1 R 3 NC(=O)-, or (C1-C 6 alkyl)SO2-, hetAr 2 , Ar 1 , and R 3 For equation IB, As defined in one embodiment, 2 is independent of N and O and a 5- to 6-membered heteroaryl ring having 1 to 2 ring heteroatoms selected from the group consisting of halogen, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and C1- Independently selected from the group consisting of C6 alkoxy (optionally substituted with 1-3 fluoro) The group is optionally substituted with one or more substituents as defined above.

[0424] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, and ring D teeth, [ka] and

[0425] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 C(=O)-, Ar 1 R 3 NC(= O)-, or (C1-C6 alkyl)SO2-, and hetAr 2 , Ar 1 , and R 3 is as defined for formula IB. In one embodiment of formula IB, The ring D is unsubstituted. 1 is N and X 2 , X 3 , and and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0426] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, and ring D teeth, [ka] and

[0427] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 In one embodiment of formula IB, the ring D is unsubstituted. In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 teeth , CH.

[0428] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3is N and X 2 and X 4 is CH and A is CN and B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, and ring D teeth, [ka] and

[0429] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C (=O)- and hetAr 2 is as defined for formula IB. In one embodiment of B, ring D is unsubstituted. 1 teeth N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0430] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1and X 3 is N and X 2 and X 4 is CH and A is CN and B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, and ring D teeth, [ka] and

[0431] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is Ar 1 R 3 NC (=O)- and Ar 1 is as defined for formula IB. In one embodiment, the ring D is unsubstituted. 1 is N Ri, X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 teeth, N and X 2 and X 4 is CH.

[0432] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, and ring D teeth, [ka] and

[0433] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; E is optionally substituted with an alkylidene ring, or (c) an oxo group; In one embodiment of Formula IB, Ring D is unsubstituted. In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH. In an embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0434] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C6 alkyl- or hydroxyC2-C6 alkyl-, wherein the alkyl moiety is C HydroxyC2-C6 alkyl optionally substituted with a 3-C6 cycloalkylidene ring - and ring D is [ka] and

[0435] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 C(=O)-, Ar 1 R 3 NC(= O)-, or (C1-C6 alkyl)SO2-, and hetAr 2 , Ar 1 , and R 3 is as defined for formula IB. In one embodiment, ring D is substituted In one embodiment, X1 is N and X 2 , X 3 , and X 4 is CH In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH be.

[0436] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C alkyl-, and ring D is [ka] and

[0437] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2C1-C6 alkyl, hetAr 2 C(=O)-, Ar 1 R 3 NC(= O)-, or (C1-C6 alkyl)SO2-, and hetAr 2 , Ar 1 , and R 3 is as defined for formula IB. In one embodiment, the ring D is In one embodiment, X 1 is N and X 2 , X 3 , and X 4 teeth, In one embodiment, X is CH. 1 and X 3 is N and X 2 and X 4 is C It's H.

[0438] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0439] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 C(=O)-, Ar 1 R 3 NC(= O)-, or (C1-C6 alkyl)SO2-, and hetAr 2 , Ar 1 , and R 3 is as defined for formula IB. In one embodiment, the ring D is In one embodiment, X 1 is N and X 2 , X 3 , and X 4 teeth, In one embodiment, X is CH. 1 and X 3 is N and X 2 and X 4 is C It's H.

[0440] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hetAr 1C1-C3 alkyl-, hetAr 1 is expressed in equation IB. and ring D is as defined above. [ka] and

[0441] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 C(=O)-, Ar 1 R 3 NC(= O)-, or (C1-C6 alkyl)SO2-, and hetAr 2 , Ar 1 , and R 3 is as defined for formula IB. In one embodiment, the ring D is In one embodiment, X 1 is N and X 2 , X 3 , and X 4 teeth, In one embodiment, X is CH. 1 and X 3 is N and X 2 and X 4 is C It's H.

[0442] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (hetCyc a ) C1-C3 alkyl-, hetCyc a is the expression as defined for IB, and ring D is [ka] and

[0443] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 C(=O)-, Ar 1 R 3 NC(= O)-, or (C1-C6 alkyl)SO2-, and hetAr 2 , Ar1 , and R 3 is as defined for formula IB. In one embodiment, the ring D is In one embodiment, X 1 is N and X 2 , X 3 , and X 4 teeth, In one embodiment, X is CH. 1 and X 3 is N and X 2 and X 4 is C It's H.

[0444] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0445] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 is defined for formula IB In one embodiment, the ring D is unsubstituted. Hey, hetAr 2 has 1 to 2 ring heteroatoms independently selected from N and O. and a 5- to 6-membered heteroaryl ring having halogen, C1-C6 alkyl (1 to 3 fluoro), and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). optionally substituted with one or more substituents independently selected from the group consisting of In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH .

[0446] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0447] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C (=O)- and hetAr 2 is as defined for formula IB. In one embodiment, the ring D is unsubstituted. 2 teeth, 5-6 membered heteroaryl having 1-2 ring heteroatoms independently selected from N and O a halogen ring and optionally substituted with halogen, C1-C6 alkyl (1 to 3 fluoro) and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). In one embodiment, the alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1and X 3 is N and X 2 and X 4 is CH.

[0448] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0449] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is Ar 1 R 3 NC (=O)- and Ar 1 and R 3 is as defined for formula IB. In one embodiment, ring D is unsubstituted. 1 is N, X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N Yes, X 2 and X 4 is CH.

[0450] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0451] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; E is optionally substituted with an alkylidene ring, or (c) an oxo group; In one embodiment, the ring D is unsubstituted. In terms of form, X 1is N and X 2 , X 3 , and X 4 is CH. In one embodiment Hey, X 1 and X 3 is N and X 2 and X 4 is CH.

[0452] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C alkyl-, and ring D is [ka] and

[0453] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr2 C(=O)-, Ar 1 R 3 NC(= O)-, or (C1-C6 alkyl)SO2-, and hetAr 2 , Ar 1 , and R 3 is as defined for formula IB. In one embodiment, the ring D is In one embodiment, X 1 is N and X 2 , X 3 , and X 4 teeth, In one embodiment, X is CH. 1 and X 3 is N and X 2 and X 4 is C It's H.

[0454] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C alkyl-, and ring D is [ka] and

[0455] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 is defined for formula IB In one embodiment, the ring D is unsubstituted. Hey, hetAr 2 has 1 to 2 ring heteroatoms independently selected from N and O. and a 5- to 6-membered heteroaryl ring having halogen, C1-C6 alkyl (1 to 3 fluoro), and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). optionally substituted with one or more substituents independently selected from the group consisting of In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH .

[0456] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C alkyl-, and ring D is [ka] and

[0457] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C (=O)- and hetAr 2 is as defined for formula IB. In one embodiment, the ring D is unsubstituted. 2 teeth, 5-6 membered heteroaryl having 1-2 ring heteroatoms independently selected from N and O a halogen ring and optionally substituted with halogen, C1-C6 alkyl (1 to 3 fluoro) and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). In one embodiment, the alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3is N and X 2 and X 4 is CH.

[0458] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C alkyl-, and ring D is [ka] and

[0459] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is Ar 1 R 3 NC (=O)- and Ar 1 and R 3 is as defined for formula IB. In one embodiment, ring D is unsubstituted. 1 is N, X 2 , X 3 , and X 4is CH. In one embodiment, X 1 and X 3 is N Yes, X 2 and X 4 is CH.

[0460] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C alkyl-, and ring D is [ka] and

[0461] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; E is optionally substituted with an alkylidene ring, or (c) an oxo group; In one embodiment, ring D is unsubstituted. Hey, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment , X1 and X 3 is N and X 2 and X 4 is CH.

[0462] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, and ring D is [ka] and

[0463] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisman indicates the point of attachment to E, where E is a hetAr 2 C1-C6 alkyl, the alkyl moiety is optionally substituted with 1 to 3 fluoro groups, 2 C1-C6A Rukill, or hetAr 2 C(=O) and hetAr 2 is halogen and C1 -C6 alkoxy (optionally substituted with 1 to 3 fluoro), optionally substituted with one or more substituents selected from the group consisting of: 2 C(=O) and h etAr 2 is as defined for formula IB. In one embodiment, X 1 teeth N and X 2 , X 3 , and X4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0464] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, and ring D is [ka] and

[0465] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisman indicates the point of attachment to E, where E is a hetAr 2 C1-C6 alkyl, The alkyl moiety is optionally substituted with 1 to 3 fluoro groups, and 2 is a halogen and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro). hetAr optionally substituted with one or more independently selected substituents 2 C1-C6 alkyl, hetAr 2 is as defined for formula IB. In this state, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0466] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, and ring D is [ka] and

[0467] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisman indicates the point of attachment to E, where E is a hetAr 2 C(=O) and hetAr 2 is optionally substituted with halogen and C1-C6 alkoxy (1 to 3 fluoro) hetA is optionally substituted with one or more substituents independently selected from the group consisting of r 2 C(=O) and hetAr 2 is as defined for formula IB. In an embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH. In this state, X 1 and X 3 is N and X 2 and X4 is CH.

[0468] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0469] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisk indicates the point of attachment to E, and E is Ar 1 N(R 3 )C(=O) and Ar 1 oh Yobi R 3 is as defined for formula IB. In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0470] In one embodiment of formula IB, X 1 is N and X 2 , X3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0471] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisman indicates the point of attachment to E, where E is a hetAr 2 C1-C6 alkyl- the alkyl portion is optionally substituted with 1 to 3 fluoro; 2 C1-C6 Alkyl-, or hetAr 2 C(=O) and hetAr 2 For equation IB, As defined above. In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0472] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0473] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisman indicates the point of attachment to E, where E is a hetAr 2 C1-C6 alkyl- the alkyl portion is optionally substituted with 1 to 3 fluoro; 2 C1-C6 Alkyl-, hetAr 2 is as defined for formula IB. In terms of form, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment Hey, X 1 and X 3 is N and X 2 and X 4 is CH.

[0474] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0475] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisman indicates the point of attachment to E, where E is a hetAr 2 C(=O)- and hetAr 2 is as defined for formula IB. In one embodiment, X 1 is N , X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0476] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0477] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisman indicates the point of attachment to E, where E is a hetAr 2 C1-C6 alkyl- the alkyl portion is optionally substituted with 1 to 3 fluoro; 2 C1-C6 Alkyl-, hetAr 2 is as defined for formula IB. In terms of form, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment Hey, X 1 and X 3 is N and X 2 and X 4 is CH.

[0478] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hydroxyC2-C6 alkyl-, the alkyl portion being C3-C6 hydroxyC2-C6 alkyl- optionally substituted with a cycloalkylidene ring; , ring D is [ka] and

[0479] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The talisman indicates the point of attachment to E, where E is a hetAr 2 C1-C6 alkyl- the alkyl portion is optionally substituted with 1 to 3 fluoro; 2 C1-C6 Alkyl-, hetAr 2 is as defined for formula IB. In terms of form, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment Hey, X 1 and X 3 is N and X 2 and X 4 is CH.

[0480] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hetAr 1 C1-C3 alkyl-, hetAr 1 is expressed in equation IB. and ring D is as defined above. [ka] and

[0481] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 is defined for formula IB In one embodiment, ring D is unsubstituted. Te, hetAr 2 has 1 to 2 ring heteroatoms independently selected from N and O and a 5- to 6-membered heteroaryl ring containing halogen, C1-C6 alkyl (1 to 3 fluorines). C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro) and optionally substituted with one or more substituents independently selected from the group consisting of In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0482] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hetAr 1 C1-C3 alkyl-, hetAr 1 is expressed in equation IB. and ring D is as defined above. [ka] and

[0483] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C (=O)- and hetAr 2 is as defined for formula IB. In one embodiment, ring D is unsubstituted. 2 Ha, N 5-6 membered heteroaryl having 1-2 ring heteroatoms independently selected from and O ring and optionally substituted with halogen, C1-C6 alkyl (1-3 fluoro ), and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro) In one embodiment, the aryl group is optionally substituted with one or more substituents independently selected from , X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0484] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hetAr 1 C1-C3 alkyl-, hetAr 1 is expressed in equation IB. and ring D is as defined above. [ka] and

[0485] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is Ar 1 R 3 NC (=O)- and Ar 1 and R 3 is as defined for formula IB. In one embodiment, ring D is unsubstituted. 1 is N, X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N Yes, X 2 and X 4 is CH.

[0486] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is hetAr 1 C1-C3 alkyl-, hetAr 1 is expressed in equation IB. and ring D is as defined above. [ka] and

[0487] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; E is optionally substituted with an alkylidene ring, or (c) an oxo group; In one embodiment, ring D is unsubstituted. In X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment Te, X 1 and X 3 is N and X 2 and X 4 is CH.

[0488] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (hetCyc a ) C1-C3 alkyl-, hetCyc a is the expression as defined for IB, and ring D is [ka] and

[0489] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C 1-C6 alkyl, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 is defined for formula IB In one embodiment, ring D is unsubstituted. Te, hetAr 2 has 1 to 2 ring heteroatoms independently selected from N and O and a 5- to 6-membered heteroaryl ring containing halogen, C1-C6 alkyl (1 to 3 fluorines). C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro) and optionally substituted with one or more substituents independently selected from the group consisting of In one embodiment, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0490] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (hetCyc a ) C1-C3 alkyl-, hetCyc a is the expression as defined for IB, and ring D is [ka] and

[0491] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is a hetAr 2 C (=O)- and hetAr 2 is as defined for formula IB. In one embodiment, ring D is unsubstituted. 2 Ha, N 5-6 membered heteroaryl having 1-2 ring heteroatoms independently selected from and O ring and optionally substituted with halogen, C1-C6 alkyl (1-3 fluoro ), and C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro) In one embodiment, the aryl group is optionally substituted with one or more substituents independently selected from , X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 and X 4 is CH.

[0492] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (hetCyc a ) C1-C3 alkyl-, hetCyc a is the expression as defined for IB, and ring D is [ka] and

[0493] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) an oxo group, and E is Ar 1 R 3 NC (=O)- and Ar 1 and R 3 is as defined for formula IB. In one embodiment, ring D is unsubstituted. 1 is N, X2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X 3 is N Yes, X 2 and X 4 is CH.

[0494] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 is CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN and B is (hetCyc a ) C1-C3 alkyl-, hetCyc a is the expression as defined for IB, and ring D is [ka] and

[0495] In the formula, the wavy line represents X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The tali risk indicates the point of attachment to E, and ring D is (a) halogen, OH, 1 to 3 fluoro C1-C3 alkyl optionally substituted with, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; E is optionally substituted with an alkylidene ring, or (c) an oxo group; In one embodiment, ring D is unsubstituted. In X 1 is N and X2 , X 3 , and X 4 is CH. In one embodiment Te, X 1 and X 3 is N and X 2 and X 4 is CH.

[0496] In one embodiment, Formula I comprises a compound of formula IC, wherein:

[0497] X 1 , X 2 , X 3 , and X 4 are independently CH, CF, or N, and X 1 , X 2 , X 3 , and X 4 0, 1, or 2 of are N,

[0498] A is H, CN, Cl, CH3-, CH3CH2-, cyclopropyl, -CH2CN, or -CH(CN)CH3,

[0499] B is

[0500] (a) hydrogen,

[0501] (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro;

[0502] (c) hydroxyC2-C6 alkyl-, wherein the alkyl moiety is C3-C6 cycloalkyl. dihydroxyC3-C6 alkyl-, optionally substituted with an alkylidene ring;

[0503] (d) dihydroxyC3-C6 alkyl-, wherein the alkyl moiety is C3-C6 cyclo dihydroxyC3-C6 alkyl-, optionally substituted on the alkylidene ring;

[0504] (e) (C1-C6 alkoxy)C1-C6 alkoxy optionally substituted with 1 to 3 fluoro groups kill-,

[0505] (f)(R 1 R 2 N)C(=O)C1-C6 alkyl-, where R 1 and R 2 becomes independent and H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro). , (R 1 R 2 N)C(=O)C1-C6 alkyl-,

[0506] (g)hetAr 1 C1-C3 alkyl-, where hetAr 1 But N, O, and S and a 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from and optionally substituted with one or more independently selected C1-C6 alkyl substituents; hetAr 1 C1-C3 alkyl-,

[0507] (h) (C3-C6 cycloalkyl)C1-C3 alkyl-,

[0508] (i)(hetCyc a ) C1-C3 alkyl-, or

[0509] (j)hetCyc a , and

[0510] hetCyc a has 1 to 2 ring heteroatoms independently selected from N and O and OH, C1-C6 alkyl (optionally 1 to 3 fluoro) optionally substituted) or hydroxyC1-C6 alkyl-,

[0511] Ring D is [ka]

[0512] In the formula, the wavy line represents X of ring D. 1 , X 2 , X 3 , and X 4 indicates the point of attachment to the ring containing the asymmetric group; The talisk indicates the point of attachment to E,

[0513] E is

[0514] (a) hydrogen,

[0515] (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro;

[0516] (d) (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is 1 to 3 Fluoro or R g R h N-substituent (wherein R g and R h are independently H or C (C1-C6 alkyl)C(=O) optionally substituted with (C1-C6 alkyl)C(=O) -,

[0517] (f) (C1-C6 alkoxy)C(=O),

[0518] (l)hetAr 2 C(=O)-,

[0519] (o)R 3 R 4 NC(=O)-,

[0520] (s)Ar 1 SO2-,

[0521] (t)hetAr 2 SO2-,

[0522] (v)Ar 1 C(=O)-,

[0523] (cc)hetAr 2 ,or

[0524] (dd) C3-C6 cycloalkyl;

[0525] R 3 is H or C1-C6 alkyl;

[0526] R 4 is C1-C6 alkyl.

[0527] In one embodiment of formula IC, X 1 is N and X 2 , X 3 , and X 4 is CH be.

[0528] In one embodiment of formula IC, A is CN.

[0529] In one embodiment of formula IC, X 1 is N and X 2 , X 3 , and X 4 is CH and A is CN.

[0530] In one embodiment of formula IC, B is optionally substituted with 1 to 3 fluoro (C1 -C6 alkoxy) C1-C6 alkyl, or hydroxy C2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. oxyC2-C6 alkyl-.

[0531] In one embodiment of formula IC, B is optionally substituted with 1 to 3 fluoro (C1 In one embodiment of formula IC, B is: (C1-C6 alkoxy)C2-C6 alkyl optionally substituted with 1 to 3 fluoro be.

[0532] In one embodiment of formula IC, B is hydroxyC2-C6 alkyl- In one embodiment, the alkyl moiety is optionally substituted with a C3-C6 cycloalkylidene ring. wherein the alkyl portion of the B group is unsubstituted.

[0533] In one embodiment of formula IC, X 1 is N and X 2 , X 3 , and X 4 is CH A is CN and B is a C1-C6 alkoxy optionally substituted with 1-3 fluoro groups. oxy)C1-C6 alkyl.

[0534] In one embodiment of formula IC, X 2 is N and X 1 , X 3 , and X 4 is CH A is CN and B is hydroxyC2-C6 alkyl-, hydroxy C2-C6 alkyl optionally substituted with a C3-C6 cycloalkylidene ring; E is (C1-C6 alkoxy)C(=O)-.

[0535] In one embodiment of formula IC, X 1 is N and X 2 , X 3 , and X 4 is CH A is CN and B is hydroxyC2-C6 alkyl-, hydroxy C2-C6 alkyl optionally substituted with a C3-C6 cycloalkylidene ring; In one embodiment, the alkyl portion of the B group is unsubstituted.

[0536] The compounds of formula I include pharmaceutically acceptable salts thereof. In addition, the compounds of formula I may also be used in combination with other compounds, such as acetaminophen, benzodiazepines ... The compounds of formula I are not necessarily pharmaceutically acceptable salts, but may be used in the preparation and / or purification of the compounds of formula I. and / or as intermediates for separating the enantiomers of the compound of formula I. The pharmaceutically acceptable salts of the compounds of Formula I are not limited to those salts which may be used in the present invention. Typical examples are monohydrochloride, dihydrochloride, trifluoroacetate, and di-trifluoroacetate. In one embodiment, the compound of formula I is a trifluoroacetic acid and a disalt. Contains acid salts.

[0537] The compounds of formula I or their salts may be isolated in the form of a solvate and therefore may optionally be It will be further understood that any such solvates are included within the scope of the present invention. The compounds of formula I and their salts can be prepared by dissolving them in a pharmaceutically acceptable solvent such as water, ethanol, etc. It can exist in unsolvated and solvated forms.

[0538] In one embodiment, the compounds of formula I include the compounds of Examples 1-561 and their derivatives. This includes isomers and pharmaceutically acceptable salts and solvates. The compounds of Examples 1-561 are in the free base form. The compound of ∼561 is the dihydrochloride and trifluoroacetate salt.

[0539] The term "pharmaceutically acceptable" means that a compound or its salt or composition is and / or other ingredients and / or patients treated therewith. indicates that it is compatible with

[0540] The compounds provided herein also contain a hydroxyl group at one or more of the atoms that constitute such compounds. In particular, compounds according to Formula I may contain unnatural proportions of atomic isotopes. When referring to a compound, the atoms may be any of the natural, naturally occurring or synthetically produced elements. All isotopes and isotopic mixtures of that atom, either in natural abundance or in isotopically enriched form For example, when hydrogen is mentioned, it includes 1 H, 2 H, 3 H or mixtures thereof and when carbon is mentioned, it is understood to refer to 11 C. 12 C. 13 C. 14 C or mixtures thereof, and when nitrogen is mentioned it means 13 N, 14 N , 15 N or mixtures thereof, and when oxygen is mentioned, it is understood to refer to 14 O. 15 O. 16 O. 17 O. 18 Fluorocarbons are understood to refer to fluorocarbons or mixtures thereof. When is mentioned, it means 18 F, 19 F or mixtures thereof. Thus, the compounds provided herein also contain one or more non-radioactive atoms that are not part of the radioactive of one or more atoms, including radioactive compounds, that have been replaced by one of their enriched isotopes Radiolabeled compounds also include compounds with one or more isotopes. ), research reagents (e.g., assay reagents), and diagnostic agents (e.g., in vivo imaging agents). All isotopic variations of the compounds provided herein, whether radioactive or not, are useful. Regardless, they are intended to be included within the scope of the present invention.

[0541] For illustrative purposes, Schemes 1-6 illustrate the compounds provided herein and important General methods for preparing intermediates are shown. For a more detailed description of the individual reaction steps, see See the Examples section below. Those skilled in the art will recognize that other synthetic routes may be used to synthesize the compounds of the present invention. It will be appreciated that certain starting materials and reagents may be used in the schemes. While shown and discussed below, other starting materials and reagents may be readily substituted to allow for a variety of derivatives. In addition, many of the compounds prepared by the methods described below may be prepared by providing the conductors and / or reaction conditions. The compounds may be further modified in light of this disclosure using convenient chemistry well known to those skilled in the art. It is possible. [ka]

[0542] Scheme 1 shows a general scheme for the synthesis of compound 12, where A is CN and B is X 1 , X 2 , X 3 , X 4 , rings D and E are as defined for formula I.

[0543] Compound 2 was prepared by converting commercially available 3-bromo-5-methoxypyridine (compound 1) into O-( It can be obtained by treating with mesitylsulfonylhydroxylamine. Sulfonylhydroxylamine is prepared by Mendiola, J., et al., Org. Process Res.Dev.2009,13(2),263-267 Compound 2 may be prepared by reacting it with ethyl propiolate to give compound 3A. and 3B, which are typically in a ratio of about 2:1 to 9:1, respectively. The mixture of compounds 3A and 3B was treated with 48% HBr at elevated temperature, followed by recrystallization. After crystallization or chromatographic purification, compound 4A was obtained as the minor isomer and the major isomer. Compound 4B can be isolated by treating compound 4A with POCl3. Compound 5 can be obtained by converting the formyl group to an oxime group using NH2OH. Compound 6 can be obtained by converting the oxime group to a nitrile group using acetic anhydride. Compound 7 can be obtained by cleaving the methoxy group of compound 7 with aluminum trichloride. The hydroxy group can be converted to a hydroxy group by treatment with methylammonium chloride to give compound 8.

[0544] To prepare compound 12 where B is hydrogen, compound 12 can be prepared by converting compound 8 to the corresponding borohydride. Phosphate ester compound 10 (rings D, X) 1 , X 2 , X 3 , and X 4 is defined for Formula I As stated above, P 1 is an amino protecting group and Z is -B(OR x )(OR y ) R z and R y is H or (1-6C) alkyl, or R x and R y are, together with the atom to which they are attached, selected from (C1-C3 alkyl) forming a 5- or 6-membered ring optionally substituted with 1 to 4 substituents, and prepared by suitable palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling. coupling reaction conditions (e.g., palladium catalyst, and optionally, in dioxane at elevated temperature) using an inorganic base, e.g., Pd(PPh3)4 and a ligand in the presence of Na2CO3 Compound 11a can be obtained by the above reaction. 1 The standard The Boc group can be removed by treating compound 11a with acidic conditions, e.g., HCl. (which can be removed by the method described above) to give compound 12, where B is hydrogen and E is hydrogen. Alternatively, the deprotected ring D can be functionalized (i.e., reacted with a suitable reagent) to give or treatment) to introduce the E group under standard conditions as described below, where B is hydrogen and E Compound 12, wherein E is as defined for formula I, except that is not hydrogen. can be obtained.

[0545] Alternatively, compound 12 is prepared where B is as defined for formula I except for hydrogen. To achieve this, compound 11a is reacted with a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. -OH, hydroxy C2-C6 alkyl-OH, dihydroxy C3-C6 alkyl-OH , (C1-C6 alkoxy)C1-C6 alkyl optionally substituted with 1 to 3 fluoro -X, (R 1 R 2 N) C1-C6 alkyl-OH (wherein R 1 and R 2 Regarding formula I (as defined in 1 C1-C3 alkyl-OH, (C3-C6 alkyl chloroalkyl)C1-C3 alkyl-OH, (hetCyc a )C1-C3 alkyl-O H, or hetCyc a -OH(where hetAr 1 and hetCyc a is expressed in Eq. and reacting each of the reagents with a reagent such as a methyl group (as defined for the Mitsunobu reaction conditions) Optionally protected by a protecting group under certain conditions (e.g., PPh3 and diisopropyl azodicarboxylate). to give compound 11. Compound 12 can then be converted to compound 12 by the same procedure as above. It can be prepared from 11 followed by removal of the protecting group on B, if present.

[0546] Another method for preparing compound 12, wherein B is as defined for formula I except for hydrogen, is As a method, compound 9 is reacted with a suitable base (e.g., a metal alkali carbonate such as potassium carbonate) to form a cyclohexane-1,2-diol-1-one. Compound 8 is reacted with a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups in the presence of alkyl-X, hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl-X, (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1 to 3 fluoro X, (R 1 R 2 N) C1-C6 alkyl-X (wherein R 1 and R 2 is defined for Formula I (as defined), hetAr 1 C1-C3 alkyl-X, (C3-C6 cycloa C1-C3 alkyl-X, (hetCyc a ) C1-C3 alkyl-X, or hetCyc a -X(where hetAr 1 and hetCyc a is defined for Formula I where X is a leaving atom or group (such as a halide or triflate). The compound can be prepared by reacting the compound with a reagent such as a Protecting groups (e.g., t-butyldihydroxyl groups when the B group has one or two additional hydroxy groups) For example, B is optionally substituted with 1 to 3 fluoro groups. When the compound 9 is a C1-C6 alkyl substituted compound, the compound 9 can be prepared by converting the compound 8 into a C1-C6 alkyl substituted compound. -X, wherein the alkyl is optionally substituted with 1 to 3 fluoro, and X is B a halogen such as r or Cl, or a leaving group such as triflate, Compound 11 can then be prepared by reacting with the appropriate Suitable palladium-catalyzed cross-coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g. For example, a palladium catalyst and, optionally, an inorganic base, Pd(PPh3), in dioxane at elevated temperature 4 and Na2CO3) to convert compound 9 to the corresponding boronic acid ester. Compound 10 can then be prepared by coupling with ester compound 11. Compound 12 is prepared from compound 11 as described above, followed by removal of the protecting group on B, if present. can be removed. [ka]

[0547] Scheme 2 shows another general scheme for the synthesis of compound 12, where A is CN; B, X 1 , X 2 , X 3 , X 4 , rings D and E are as defined for formula I.

[0548] Compound 9, wherein B is as defined for Formula I (e.g., as described in Scheme 1). (prepared as above) to afford the corresponding boronic ester compound 13 (X 1 , X 2 , X 3 , and and X 4is as defined for formula I, and L 2 is a triflate or halogen Z is a leaving group such as -B(OR x )(OR y ) and R z and R y teeth, H or (1-6C) alkyl, or R x and R y are combined optionally, 1 to 4 substituents selected from (C1-C3 alkyl), together with the atom in question; to form an optionally substituted 5- or 6-membered ring) to form an appropriate palladium-catalyzed chloroform. Coupling reaction conditions, such as Suzuki coupling reaction conditions (e.g., palladium catalyst and optionally an inorganic base, such as Pd(PPh3)4 and (ligand in the presence of Na2CO3) to give compound 14. 16 is prepared by converting compound 14 to the appropriate S N Under Ar conditions (e.g., optionally with a base such as K2CO3 and at elevated temperature), wherein ring D is as defined for formula I and P 1 Gaami The compound can be prepared by coupling with compound 15, which is a hydroxyl group-protecting group.

[0549] The protecting group P on the ring D of compound 16 1 is removed under standard conditions (e.g., the Boc group is Compound 1 can be removed by treatment with acidic conditions, e.g., HCl), E Alternatively, the deprotected ring D can be functionalized to give compound 12, where (i.e., reacting or treating with a suitable reagent) to convert the E group to and E is as defined for formula I, except that E is not H. Compound 12 can be obtained. [ka]

[0550] Scheme 3 shows a general scheme for the synthesis of compound 21, where A is H; B, X 1 , X 2 , X 3 , X 4 , rings D and E are as defined for formula I.

[0551] Compound 18 can be prepared by suitable palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling. Pulling reaction conditions (e.g., palladium catalyst, and optionally, free radical polymerization in dioxane at elevated temperature) Using a ligand in the presence of an organic base, e.g., Pd(PPh3)4 and Na2CO3 Compound 4A (prepared, for example, as described in Scheme 1) can be converted to the corresponding boronic acid ester. Stereo compound 10 (wherein rings D and X 1 , X 2 , X 3 and X 4 is defined for Formula I As stated above, P 1 is an amino protecting group and Z is -B(OR x )(OR y ) and R z and R y is H or (1-6C) alkyl, or R x and R y teeth, together with the atom to which they are attached, one to one selected from (C1-C3 alkyl) By coupling with Compound 19 can be prepared by treating compound 18 with aluminum trichloride. It can be prepared by:

[0552] To prepare compound 12, where B is as defined for formula I except for hydrogen, Compound 20 can be prepared by converting compound 19 into a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl-X, 1 (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 3 fluoro , (R 1 R 2 N) C1-C6 alkyl-X (wherein R 1 and R 2 is defined for formula I (As stated), hetAr 1 C1-C3 alkyl-X, (C3-C6 cycloalky C1-C3 alkyl-X, (hetCyc a ) C1-C3 alkyl-X, or h etCyc a -X(where hetAr 1 and hetCyc a is defined for Formula I where X is a leaving atom or group (such as a halide or triflate). Each of the reagents can be prepared by reacting the compound with a protecting group. groups (e.g., t-butyldimethyl when the B group has one or two additional hydroxy groups). For example, B is optionally substituted with 1 to 3 fluoro groups. When X is C1-C6 alkyl, compound 19 can be prepared by adding C1-C6 alkyl-X to The alkyl is optionally substituted with 1 to 3 fluoro groups, and X is Br or Cl, etc. reacted with a C1-C6 alkyl-X, a leaving group such as a halogen or triflate Compound 20 can be prepared by adding a protecting group P on the ring D of compound 20. 1 The standard The Boc group can be removed under acidic conditions (e.g., by treating compound 20 with HCl). (This can be removed by cleaving the aryl group) to give compound 21 where E is H. Alternatively, the deprotected ring D of compound 21 can be functionalized (i.e., reacted with a suitable reagent) or treatment) to introduce the E group under standard conditions as described below, provided that E is not H. With the exception of E, compound 21 can be obtained, where E is as defined for formula I.

[0553] Alternatively, compound 21 is prepared where B is as defined for formula I except for hydrogen. To achieve this, compound 19 is treated with a C1-C6 alkyl- OH, hydroxyC2-C6 alkyl-OH, optionally substituted with 1 to 3 fluoro ( C1-C6 alkoxy)C1-C6 alkyl-X, (R1R2N)C1-C6 alkyl- OH (in the formula, R 1 and R 2 is as defined for Formula I), hetAr 1 C1-C3 alkyl-OH, (C3-C6 cycloalkyl)C1-C3 alkyl-OH, (hetCyc a ) C1-C3 alkyl-OH, or hetCyc a -OH(in the formula, h etAr 1 and hetCyc a is as defined for formula I) and each of the reagents is reacted under Mitsunobu reaction conditions (e.g., PPh and diisopropyl azodicarboxylate) to give compound 20. Compound 21 is then prepared from compound 20 as described above, followed by the addition of, if present, The protecting group on B can be removed.

[0554] When group B is hydrogen, compound 21 can be prepared by deprotection and optional functionalization as described herein. It can be prepared from compound 19 according to the procedure described above. [ka]

[0555] Scheme 4 shows an alternative general scheme for the synthesis of compound 21, where A is H. Ri, B, X 1 , X 2 , X 3 , X 4 and rings D and E are as defined for formula I. do.

[0556] Compound 22 can be prepared by trichloroethylene from compound 4A (prepared, for example, as described in Scheme 1). It can be prepared by treatment with aluminum chloride.

[0557] To prepare compound 21 where B is hydrogen, compound 19 is reacted with an appropriate palladium catalyst to prepare compound 21. Ross coupling reaction conditions, e.g., Suzuki coupling reaction conditions (e.g., palladium catalyst) a solvent, and optionally an inorganic base, such as Pd(PPh3)4 and and Na2CO3) to convert compound 22 to the corresponding boronic acid ester. Compound 10 (rings D and X) 1 , X 2 , X 3 , and X 4 is as defined for Formula I and P 1 is an amino protecting group and Z is -B(OR x )(OR y ) and R z oh Yobi R y is H or (1-6C) alkyl, or R x and R y Is that and together with the atom to which they are attached, 1 to 4 alkyl groups selected from (C1-C3 alkyl) (which forms a 5- or 6-membered ring optionally substituted with the substituents Compound 21 can be prepared from compound 19 according to the process described in Scheme 3. It can be prepared from

[0558] Alternatively, compound 21 is prepared where B is as defined for formula I except for hydrogen. To achieve this, compound 23 can be prepared by converting compound 22 to a C1- C6 alkyl-X, hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl X, (C1-C6 alkoxy)C1-C6 alkyl optionally substituted with 1 to 3 fluoro Rukill-X, (R 1 R 2 N) C1-C6 alkyl-X (wherein R 1 and R 2 is expressed in Eq. (as defined for 1 C1-C3 alkyl-X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc a )C1-C3 alkyl-X , or hetCyc a -X(where hetAr 1 and hetCyc a Regarding formula I X is a leaving atom or group (e.g., a halide or triflate) and the like), each of which is a Each may be provided with a protecting group (e.g., t- when the B group has one or two additional hydroxy groups). butyldimethylsilyl group). For example, B is 1 to 3 fluoro groups. When optionally substituted C1-C6 alkyl, compound 23 can be replaced by C1-C6 alkyl- X, wherein the alkyl is optionally substituted with 1 to 3 fluoro, and X is Br or is a halogen such as Cl, or a leaving group such as triflate, C1-C6 alkyl- Compound 20 can be prepared by reacting X with X as described in Scheme 3. Compound 23 can be coupled with compound 10 to prepare Compound 21 can be prepared from compound 20 according to the process described in Scheme 3. It is possible.

[0559] Alternatively, compound 21 is prepared where B is as defined for formula I except for hydrogen. To achieve this, compound 19 is treated with a C1-C6 alkyl- OH, hydroxyC2-C6 alkyl-OH, optionally substituted with 1 to 3 fluoro ( C1-C6 alkoxy)C1-C6 alkyl-X, (R1R2N)C1-C6 alkyl- OH (in the formula, R 1 and R 2 is as defined for Formula I), hetAr 1 C1-C3 alkyl-OH, (C3-C6 cycloalkyl)C1-C3 alkyl-OH, (hetCyc a ) C1-C3 alkyl-OH, or hetCyc a -OH(in the formula, h etAr 1 and hetCyc a is as defined for formula I) and each of the reagents is reacted under Mitsunobu reaction conditions (e.g., PPh and diisopropyl azodicarboxylate) to give compound 20. Compound 21 was then prepared from compound 20 as described in Scheme 3, followed by , protecting groups on B, if present, can be removed. [ka]

[0560] Scheme 5 shows an alternative general scheme for the synthesis of compound 21, where A is H. Ri, B, X 1 , X 2 , X 3 , X 4 and rings D and E are as defined for formula I. do.

[0561] Compound 22 can be prepared by trichloroethylene from compound 4A (prepared, for example, as described in Scheme 1). It can be prepared by treatment with aluminum chloride.

[0562] To prepare compound 21, where B is as defined for formula I except for hydrogen, Compound 23 can be prepared by converting compound 22 to a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl-X, 1 (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 3 fluoro , (R 1 R 2 N) C1-C6 alkyl-X (wherein R 1 and R 2 is defined for formula I (As stated), hetAr 1 C1-C3 alkyl-X, (C3-C6 cycloalky C1-C3 alkyl-X, (hetCyc a ) C1-C3 alkyl-X, or h etCyc a -X(where hetAr 1 and hetCyca is defined for Formula I where X is a leaving atom or group (such as a halide or triflate). Each of the reagents can be prepared by reacting the compound with a protecting group. groups (e.g., t-butyldimethyl when the B group has one or two additional hydroxy groups). For example, B is optionally substituted with 1 to 3 fluoro groups. When the compound is C1-C6 alkyl, the compound can be prepared by converting compound 22 into C1-C6 alkyl- X, wherein the alkyl is optionally substituted with 1 to 3 fluoro, and X is Br or is a halogen such as Cl, or a leaving group such as triflate, C1-C6 alkyl- It can be prepared by reacting with X.

[0563] Compound 24 can be prepared by suitable palladium-catalyzed cross-coupling reaction conditions, e.g., Suzuki coupling. Pulling reaction conditions (e.g., palladium catalyst, and optionally, free radical polymerization in dioxane at elevated temperature) using a ligand in the presence of an organic base, e.g., Pd(PPh3)4 and Na2CO3 Compound 23 was converted to boronic ester 13(X 1 , X 2 , X 3 , and X 4 Regarding formula I As defined by L 2 is a leaving group such as a triflate or halide Z is -B(OR x )(OR y ) and R z and R y is H or (1-6 C) alkyl or R x and R y together with the atoms to which they are attached. (C1-C3 alkyl) It can be prepared by reacting with methyltrimethylsilyl (which forms a six-membered ring).

[0564] To prepare compound 21 where B is hydrogen, compound 24 can be prepared by reacting compound 22 as described above. can be prepared by reacting with compound 13 directly.

[0565] Compound 20 can be prepared by reacting compound 24 with the appropriate S N Under Ar conditions (e.g., optionally K2CO3 In the presence of any base and at high temperatures), P 1 is an amino protecting group, It can be prepared by ring forming.

[0566] Compound 21 can be prepared from compound 20 according to the process described in Scheme 3. can. [ka]

[0567] Scheme 6 shows a general scheme for the synthesis of compound 31, where A is Cl and B, X 1 , X 2 , X 3 , X 4 , rings D and E are as defined for formula I.

[0568] Compound 25 can be prepared by trichloroethylene from compound 4A (prepared, for example, as described in Scheme 1). It can be prepared by treatment with aluminum chloride.

[0569] Compound 26 can be prepared by treating compound 25 with aluminum trichloride. can be done.

[0570] To prepare compound 31, where B is as defined for formula I except for hydrogen, Compound 27 can be prepared by converting compound 26 to a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl-X, 1 (C1-C6 alkoxy)C1-C6 alkyl-X optionally substituted with 3 fluoro , (R 1 R 2 N) C1-C6 alkyl-X (wherein R 1 and R 2 is defined for formula I (As stated), hetAr 1 C1-C3 alkyl-X, (C3-C6 cycloalky C1-C3 alkyl-X, (hetCyc a ) C1-C3 alkyl-X, or h etCyc a -X(where hetAr 1 and hetCyc a is defined for Formula I where X is a leaving atom or group (such as a halide or triflate). Each of the reagents can be prepared by reacting the compound with a protecting group. groups (e.g., t-butyldimethyl when the B group has one or two additional hydroxy groups). For example, B is optionally substituted with 1 to 3 fluoro groups. When the compound is C1-C6 alkyl, the compound can be prepared by converting compound 26 into C1-C6 alkyl- X, wherein the alkyl is optionally substituted with 1 to 3 fluoro, and X is Br or is a halogen such as Cl, or a leaving group such as triflate, C1-C6 alkyl- It can be prepared by reacting with X.

[0571] Compounds 28 (wherein the B group is methyl), 29 (wherein the B group is hydrogen), and 30 (wherein the B group is excluding hydrogen) are each suitable palladium-catalyzed cross-coupling coupling reaction conditions, e.g., Suzuki coupling reaction conditions (e.g., palladium catalyst, and optionally with an inorganic base, e.g., Pd(PPh3)4 and Na2CO3 in dioxane at elevated temperature. Compounds 25, 26, and 27 were converted to the corresponding boronic acid esters using the hydroxybenzoates (ligand in the presence of Stereo compound 10 (rings D, X 1 , X 2 , X 3 , and X 4 is defined for Formula I It is P 1 is an amino protecting group and Z is -B(OR x )(OR y ) and R z and R y is H or (1-6C) alkyl, or R x and R y teeth, together with the atom to which they are attached, one to one selected from (C1-C3 alkyl) By coupling with It can be prepared as follows.

[0572] The protecting group P on the ring D of compound 29 or 30 1 is removed under standard conditions (e.g., B The oc group can be removed by treating compound 29 or 30 with acidic conditions, such as HCl. ) to give compound 21 where E is H. Alternatively, deprotection can be performed to give compound 22. The resulting ring D can be functionalized (i.e., appropriately modified) to include an E group under standard conditions as described below. By reacting or treating with an appropriate reagent, compound 31 can be obtained, and E is not H. Except, E is as defined for formula I.

[0573] Ring D of compounds 12, 21, and 31 described in Schemes 1-6 is well known to those skilled in the art. functionalized (i.e., reacted with an appropriate reagent) to include an E group using standard chemistry available in or treated), and E is any one of the E groups defined for formula I, except for hydrogen. As used herein, the term "functionalized" means that E is either hydrogen or The compound of formula 12, 21, or 31 is reacted or treated with a suitable reagent to give the compound of formula 12, 2 1, or 31, and E is a group having the formula I except for hydrogen. As defined above.

[0574] For example, E may be (C1-C6 alkyl)C(=O) optionally substituted with 1 to 3 fluoro. )-, (hydroxyC2-C6 alkyl)C(= optionally substituted with 1 to 3 fluoro O)-, (C1-C6 alkoxy)C(=O)-, (C3-C6 cycloalkyl)C(= O)-(wherein the cycloalkyl is (C1-C6 alkoxy)C1-C6 alkyl or or 5-6 membered heterocyclic rings having 1-3 ring heteroatoms independently selected from N and O aryl ring optionally substituted), Ar 1 (C1-C6 alkyl)C(=O)-(alkyl The alkyl moiety may be OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy. (intentionally replaced), hetAr 2 (C1-C6 alkyl)C(=O)-(alkyl part The moiety is optionally substituted with OH, hydroxy C1-C6 alkyl, or C1-C6 alkoxy. (converted), or hetCyc 1 (C1-C6 alkyl)C(=O)-, Compounds of formula I can be prepared by deprotection to give compounds 12 having ring D (i.e., compounds 12 where E is hydrogen). 2) by treating with the corresponding carboxylic acid using conventional amide bond forming conditions. For example, the corresponding carboxylic acid can be treated with an activating agent (e.g., HATU) followed by the appropriate Deprotection in the presence of a base (e.g., an amine base such as DIEA) in an appropriate solvent (e.g., DMA). Compound 12 having a protective ring D (i.e., E is H) is added to obtain the functional group. Functionalized compound 12 (i.e., where E is optionally substituted with 1-3 fluoro) C1-C6 alkyl)C(=O)-, optionally substituted with 1 to 3 fluoro (hydroxy) C2-C6 alkyl)C(=O)-, (C1-C6 alkoxy)C(=O)-, (C3 -C6 cycloalkyl)C(=O)-(wherein the cycloalkyl is (C1-C6 alkoxy) ) C1-C6 alkyl- or 1 to 3 ring heterocycles independently selected from N and O Optionally substituted 5- to 6-membered heteroaryl ring having aryl atoms -, Ar 1 (C1-C 6 alkyl)C(=O)-(the alkyl portion is OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy), hetAr 2 (C1-C6 alkyl)C(=O)-(the alkyl portion is OH, hydroxyC1-C6 alkyl-, if or optionally substituted with C1-C6 alkoxy), or hetCyc 1 (C1-C 6 alkyl)C(=O)-). The same chemical properties can be obtained by functionalizing compound 21 and 31 (i.e., in this case, compounds 21 and 31, respectively, E is 1 to 3 (C1-C6 alkyl)C(=O)- optionally substituted with fluoro, 1 to 3 fluoro (hydroxyC2-C6 alkyl)C(=O)-, (C1-C6 alkyl) optionally substituted with (C3-C6 cycloalkyl)C(=O)- (wherein the cyclo Alkyl is (C1-C6 alkoxy)C1-C6 alkyl- or independently of N and O Optionally substituted 5- to 6-membered heteroaryl ring having 1 to 3 ring heteroatoms selected from (Also known as Ar 1 (C1-C6 alkyl)C(=O)-(The alkyl part is OH, hydroxyl optionally substituted with hydroxyC1-C6 alkyl- or C1-C6 alkoxy ), hetAr 2 (C1-C6 alkyl)C(=O)-(alkyl part is OH, hydro optionally substituted with oxyC1-C6 alkyl- or (C1-C6)alkoxy ), or hetCyc 1 (C1-C6 alkyl)C(=O)- This can be utilized in compounds 21 and 31.

[0575] Another example is E is hetCyc 1 C(=O)- or R 3 R 4 NC(=O)- Compounds of formula I can be prepared by first obtaining the deprotected ring D of compound 12 (i.e., E is H). The ring nitrogen is activated using triphosgene in the presence of DIEA and in a solvent such as DCM. Then, the formula hetCyc 1 -H or R 3 R 4 NH (in the formula, hetCyc 1 -H, N a saturated 4- to 6-membered complex having 1 to 2 ring heteroatoms independently selected from , O, and S; The ring has at least one ring N atom, and "-H" means that a hydrogen atom is on the ring nitrogen atom. and the heterocycle is one or more independently selected C1-C6 alkoxy substituted. The functionalized compound 12 (i.e., In this case, E is hetCyc 1 C(=O)- or R 3 R 4 NC(=O)- The same chemical properties can be obtained by functionalizing compounds 21 and 31. (i.e., in this case, compounds 21 and 31, respectively, E is hetCyc 1 C(=O )- or R 3 R 4 In order to prepare N-C(=O)-, compounds 21 and 31 It can be used.

[0576] Another example is when E is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, 1 to (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 3 fluoro, A r 1 C1-C6 alkyl-, hetAr 2 C1-C6 alkyl, where the alkyl portion is optionally substituted with 1 to 3 fluoro, hetAr 2 C1-C6 alkyl, or hetCyc 1 The compound of formula I, which is C1-C6 alkyl-, can be obtained by deprotecting compound 12 ( that is, E is H) with a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. Xyl-X, (C1-C6 alkoxy)C1-C6 optionally substituted with 1 to 3 fluoro Alkyl-X, Ar 1 C1-C6 alkyl-X, hetAr 2 C1-C6 alkyl-X, or hetCyc 1 C1-C6 alkyl-X (X is Br or Cl) Treatment with the corresponding reagent in a solvent at ambient or elevated temperature in the presence of a base such as DIEA to prepare functionalized compounds 12 (i.e., where E is 1 to 3). C1-C6 alkyl optionally substituted with fluoro, C1-C6 alkyl optionally substituted with 1 to 3 fluoro (C1-C6 alkoxy)C1-C6 alkyl, Ar 1 C1-C6 alkyl-, het Ar 2 an alkyl moiety, wherein the alkyl moiety is optionally substituted with 1 to 3 fluoro; C1-C6 alkyl- or hetCyc 1 C1-C6 alkyl- 12) can be obtained. The same chemical properties can be obtained by functionalizing compounds 21 and 31 (i.e. In this case, compounds 21 and 31, respectively, E is 1 to 3 fluoro. optionally substituted C1-C6 alkyl, optionally substituted with 1 to 3 fluoro (C1- C6 alkoxy) C1-C6 alkyl-, Ar 1 C1-C6 alkyl-, hetAr 2 C 1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Iru, hetAr 2 C1-C6 alkyl-, or hetCyc 1 C1-C6 alkyl- This can be utilized with compounds 21 and 31 to prepare

[0577] Another example is when E is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with up to 3 fluoro; Ar 1 C1-C6 alkyl-, hetAr 2 C1-C6 alkyl, the alkyl portion is optionally substituted with 1 to 3 fluoro atoms, hetAr 2 C1-C6 alkyl, and hetCyc 1 C1-C6 alkyl-), the compound of formula I can be prepared by deprotecting compound 1 2 (i.e., E is H) can be converted to the corresponding aldehyde, e.g., with 1-3 fluoro optionally substituted (C1-C5 alkyl(C=O)H, optionally substituted with 1-3 fluoro (C1-C6 alkoxy)(C1-C5 alkyl)C(=O)H, Ar 1 (C1- C5 alkyl)C(=O)H, hetAr 2 (C1-C5 alkyl)C(=O)H, and hetCyc 1 (C1-C5 alkyl)-C(=O)H and a reducing agent such as NaBH( The functionalized compound 12 (i.e., when E is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with fluoro, Ar 1 C 1-C6 alkyl-, hetAr 2 C1-C6 alkyl-, wherein the alkyl portion is 1 to optionally substituted with three fluoro groups, hetAr 2 C1-C6 alkyl-, or h etCyc 1 Compound 12) can be obtained, which is a C1-C6 alkyl-. The properties of the functionalized compounds 21 and 31 (i.e., in this case, the compounds Compounds 21 and 31, E is C1-C6 alkyl optionally substituted with 1 to 3 fluoro , (C1-C6 alkoxy)C1-C6 alkyl optionally substituted with 1 to 3 fluoro -, Ar 1 C1-C6 alkyl-, hetAr 2C1-C6 alkyl-, the Ar moiety is optionally substituted with 1 to 3 fluoro groups; 2 C1-C6 alkyl Lu-, or hetCyc 1 To prepare compound 2, Available in 1 and 31.

[0578] Accordingly, a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof is also provided. Also provided herein are methods for treating rheumatoid arthritis, including:

[0579] (a) E is H and A is CN, -CHCN, or -CH(CN)CH; B, X 1 , X 2 , X 3 , X 4 and ring D is as defined in formula I. For the compound, the corresponding compound 9 has the formula: [ka]

[0580] wherein B is as defined for formula I, is reacted with the corresponding compound of formula 10 below: a boronic acid ester comprising: [ka]

[0581] In the formula, P 1 is an amino protecting group and Z is -B(OR x )(OR y ) and R x oh Yobi R y is H or C1-C6 alkyl, or R x and R y are those is, together with the atom to which it is attached, 1 to 4 substituents selected from C1-C3 alkyl Forms an optionally substituted 5- or 6-membered ring, and X 1 , X 2 , X 3 , and X 4 However, for Formula I Coupling with the corresponding boronic ester of formula 10, which is as defined, followed by , removing a protecting group, or

[0582] (b) A, B, and X, except that E is not hydrogen. 1 , X 2 , X 3 , X 4 , ring D, and For compounds of formula I, where E is as defined for formula I, the corresponding A compound having [ka]

[0583] In the formula, A, ring D, B, X 1 , X 2 , X 3 , and X 4 is defined for Formula I E 1 is hydrogen, or

[0584] (c) A is CN and rings D, B, and X 1 , X 2 , X 3 , X 4 and E is of formula I For compounds of formula I, which are as defined, the corresponding compounds of formula 14 below: So, [ka]

[0585] In the formula, B, X 1 , X2 , X 3 , and X 4 is as defined for formula I; L 2 is a leaving group or atom, the corresponding compound of formula 14 is converted to a compound of formula 15 below: So, [ka]

[0586] In the formula, P 1 is an amino protecting group, followed by reaction with a compound of formula 15, 1 of and optionally functionalizing ring D, or

[0587] (d) E is H, A is CN, and B, X 1 , X 2 , X 3 , X 4 , and ring D is of the formula For compounds of formula I, which are as defined for I, compounds of formula 14 , [ka]

[0588] In the formula, L 2 is a leaving group or atom, and B, X 1 , X 2 , X 3 , and X 4 But in Eq. by reacting a compound of formula 14, which is as defined above, with a compound of formula 15, [ka]

[0589] In the formula, P 1 is an amino protecting group, followed by coupling with a compound of formula 15 P 1 or

[0590] (e) A is H, B is H, and X 1 , X 2 , X 3 , X 4 , rings D and E are represented by formula I For compounds of formula I, which are as defined above, the compound of formula 18 below hand, [ka]

[0591] In the formula, P 1 is an amino protecting group, and X 1 , X 2 , X 3 , X 4 , ring D is defined as for formula I Compound 18 is treated with aluminum trichloride to give compound 19, which is as shown in There was, [ka]

[0592] In the formula, rings D, X 1 , X 2 , X 3 , and X 4 is as defined for formula I , P 1 is an amino protecting group, to give compound 19,

[0593] Next, the protecting group P 1 and optionally functionalizing ring D, or

[0594] (f) A is H and B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro; Hydroxy C2-C6 alkyl, dihydroxy C3-C6 alkyl, 1 to 3 fluoro (C-C alkoxy)C-C alkyl optionally substituted with (R 1 R 2N)C1 -C6 alkyl, (hetAr 1 ) C1-C3 alkyl, (C3-C6 cycloalkyl) C1-C3 alkyl, (hetCyc a ) C1-C3 alkyl, or hetCyc a and R 1 , R 2 , hetAr 1 , hetCyc a , X 1 , X 2 , X 3 , X 4 , ring D, and for compounds of formula I, where E is as defined for formula I:

[0595] A compound of formula 18: [ka]

[0596] In the formula, P 1 is an amino protecting group, and X 1 , X 2 , X 3 , X 4 , ring D is defined as for formula I Compound 18 is treated with aluminum trichloride to give compound 19, which is as shown in There was, [ka]

[0597] wherein ring D is as defined for formula I, and P 1 is an amino protecting group, and X 1 , X 2 , X 3 , and X 4 is as defined for formula I to give compound 19 To do so,

[0598] (ii) Compound 19 is reacted with a C1- C6 alkyl-X, hydroxy C2-C6 alkyl-X (wherein the alkyl portion is C3- optionally substituted with a C6 cycloalkylidene ring), dihydroxy C3-C6 alkyl -X, (C1-C6 alkoxy)C1-C6 alkoxy optionally substituted with 1 to 3 fluoro Kill X, (R 1 R 2 N)C1-C6 alkyl-X, (hetAr 1 )C1-C3 alkyl -X, (C3-C6 cycloalkyl)C1-C3 alkyl-X, (hetCyc a )C1 -C3 alkyl-X or hetCyc a -X(where R 1 , R 2 , hetAr 1 , and hetCyc a is as defined for Formula I, and X is a halide or is a leaving atom or group such as triflate) to produce compound 20, [ka]

[0599] wherein ring D is as defined for formula I, and P 1 is an amino protecting group, and X 1 , X 2 , X 3 , and X 4 is as defined for formula I, and B is 1 to 3 C1-C6 alkyl optionally substituted with fluoro, hydroxy C2-C6 alkyl, dihydroxy hydroxyC3-C6 alkyl, optionally substituted with 1 to 3 fluoro (C1-C6 alkyl koxy) C1-C6 alkyl, (R 1 R 2N) C1-C6 alkyl, (hetAr 1 )C 1-C3 alkyl, (C3-C6 cycloalkyl)C1-C3 alkyl, (hetCyc a ) C1-C3 alkyl, or hetCyc a and R 1 , R 2 , hetAr 1 , hetCyc a is as defined for formula I, to give compound 20, which is subsequently Mamoru P 1 and optionally functionalizing ring D; or

[0600] (g) A is H or Cl, B is H, and X 1 , X 2 , X 3 , X 4 , Ring D, and For compounds of formula I, wherein E and E are as defined for formula I, It is a thing, [ka]

[0601] wherein A is H or Cl, to the corresponding boronic ester of formula 10. hand, [ka]

[0602] In the formula, rings D, X 1 , X 2 , X 3 , and X 4 is as defined for formula I; P 1 is an amino protecting group, and Z is -B(OR x )(OR y ) and R z and R y H or (1-6C) alkyl, or R x and R y But they are combined and optionally substituted with 1 to 4 substituents selected from C1-C3 alkyl, together with the atom and treatment with the corresponding boronic ester of formula 10 to form a substituted 5- or 6-membered ring to give the compound of formula 19. A compound of the formula: [ka]

[0603] In the formula, rings D, X 1 , X 2 , X 3 , and X 4 is as defined for formula I; P 1 is a methyl protecting group and A is H or CL, to give a compound of formula 19, The protecting group P 1 and optionally functionalizing ring D, or

[0604] (h) A is H or Cl, and B, X 1 , X 2 , X 3 , X 4 and rings D and E are of formula I. For compounds of formula I, which are as defined above, compounds of the formula: [ka]

[0605] wherein A is H or Cl and B is as defined for formula I. , in the presence of a palladium catalyst and optionally a ligand, and in the presence of a base, to form the corresponding A boronic acid ester, [ka]

[0606] In the formula, rings D, X 1 , X 2 , X 3 , and X 4 is as defined for formula I; P 1 is an amino protecting group, and Z is -B(OR x )(OR y ) and R z and R y H or (1-6C) alkyl, or R x and R y But they are combined and optionally substituted with 1 to 4 substituents selected from C1-C3 alkyl, together with the atom Coupling with the corresponding boronic ester of formula 10 to form a substituted 5- or 6-membered ring , a compound of the formula: [ka]

[0607] In the formula, rings D, X 1 , X 2 , X 3 , X 4 and B is as defined for formula I A is H or CL, and P 1 is an amino protecting group, and then Mamoru P 1 and optionally functionalizing ring D,

[0608] (i) A is H or Cl, and B, X 1 , X 2 , X 3 , X 4 and rings D and E are of formula I. For compounds of formula I, which are as defined above, compounds of formula 24, [ka]

[0609] In the formula, L 2 is a leaving group or atom, and B, X 1 , X 2 , X 3 , and X 4 But in Eq. a compound of formula 24, which is as defined above, with a compound of formula 15, which is [ka]

[0610] In the formula, P 1 is an amino protecting group and ring D is as defined for formula I; 5 to give a compound of formula 20, [ka]

[0611] In the formula, P 1 is an amino protecting group, and rings D and X 1 , X 2 , X 3 , X 4 and B is of formula I to give a compound of formula 20, which is as defined above, followed by the addition of a protecting group P 1 Remove optionally functionalizing ring D;

[0612] If present, any additional protecting groups are removed and, optionally, a pharmaceutically acceptable salt thereof is obtained. and forming a

[0613] As used herein, the term "amino protecting group" refers to a group that is reactive with other functional groups on a compound. refers to derivatives of groups commonly used to block or protect amino groups during Examples of suitable protecting groups for use in any of the processes described herein include carbamates. mates, amides, alkyl, and aryl groups, imines, and amines, which can be removed to give the desired amines. Amino protection includes many N-heteroatom derivatives that can regenerate the amino group. Non-limiting examples of groups include acetyl, trifluoroacetyl, t-butyloxycarbonyl ( "Boc"), benzyloxycarbonyl ("CBz"), and 9-fluorenylmethyl Further examples of these and other protecting groups include fluoromethylpropional (Fmoc) and fluoromethylpropional (Fmoc). See, for example, T.W. Greene, et al., Greene's Protective Groups in Organic Synthesis.New York:Wi ley Interscience, 2006.

[0614] Hydroxy groups can be prepared by, for example, the methods described in T.W. Greene, et al., Greene's Protective Groups in Organic Synthesis.N New York: Wiley Interscience, 2006 The hydroxyl group can be protected with any convenient hydroxy protecting group, such as benzyl, Examples include trityl and silyl ethers.

[0615] The nitrogen atoms in the compounds described in any of the above methods may be selected from the group consisting of, for example, Greene & Wut s,eds.,”Protecting Groups in Organic Syn thesis”, 2 nd ed.New York;John Wiley & Sons, The nitrogen can be protected with any convenient nitrogen protecting group, as described in U.S. Patent Application Publication No. 2004 / 012991. Examples of protecting groups include t-butoxycarbonyl (BOC), phenoxycarbonyl, and Acyl and alkoxy such as [2-(trimethylsilyl)ethoxy]methyl (SEM) It contains a carbonyl group.

[0616] The ability of a test compound to act as a RET inhibitor can be determined by the assay described in Example A. It can be demonstrated. IC 50 The values ​​are shown in Table 5.

[0617] In some embodiments, the compounds provided herein exhibit potent and selective RE For example, the compounds provided herein exhibit nanomolar T inhibition against wild-type RET. showed efficacy, including the KIF5B-RET fusion and V804M gatekeeper mutation, and RET mutants are selected that have minimal activity against kinases.

[0618] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof The solvates selectively target RET kinase. For example, the compounds of Formula I or A physiologically acceptable salt or solvate may have an R 1 activity over another kinase or non-kinase target. ET kinase may be selectively targeted.

[0619] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof The solvate exhibits at least 30-fold selectivity for RET kinase over other kinases. For example, a compound of formula I, or a pharmaceutically acceptable salt or solvate thereof, can be prepared by the addition of a compound of formula I to another compound of formula I. At least 40-fold selectivity for RET kinase over β-K kinase, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity Selectivity, at least 90-fold selective, at least 100-fold selective, at least 200-fold selective selectivity, at least 300-fold selectivity, at least 400-fold selectivity, at least 50 0-fold selectivity, at least 600-fold selectivity, at least 700-fold selectivity, at least 800-fold selective, at least 900-fold selective, or at least 1000-fold selective In some embodiments, the selection for RET kinase over another kinase is Selectivity is measured in a cellular assay (e.g., a cellular assay as provided herein). It is determined.

[0620] In some embodiments, the compounds provided herein inhibit KDR kinase (e.g., For example, it can show selectivity for RET kinase over VEGFR2. In some embodiments, selectivity for RET kinase over KDR kinase is achieved by gating In some embodiments, the effect of the KIF keeper mutation is observed without abolishing the effect of the KIF keeper mutation. Selectivity over KDR kinase compared to inhibition of 5B-RET is at least 10 fold (e.g., at least 40-fold selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity, at least 90-fold selectivity Selectivity, at least 100-fold selective, at least 150-fold selective, at least 200 fold selectivity, at least 250-fold selectivity, at least 300-fold selectivity, at least 3 50-fold more selective, or at least 400-fold more selective) (i.e., the compound has a K (It was more potent against KIF5B-RET than DR). Thus, the selectivity for RET kinase over KDR kinase is approximately 30-fold. In some embodiments, selectivity for RET kinase over KDR kinase is at least In some embodiments, the expression of RET kinase over KDR kinase is at least 100-fold. In some embodiments, the selectivity for the K The selectivity for RET kinase over DR kinase is at least 400-fold. Without being bound by any theory, potent KDR kinase inhibition may be associated with the inhibition of RET-targeted malformations. This is thought to be a common feature among mitochondrial kinase inhibitors (MKIs), and the observed effects of such compounds This may be the cause of the observed dose-limiting toxicity.

[0621] In some embodiments, the inhibition of V804M is greater than that observed for wild-type RET. For example, the inhibition of V804M was within about 2-fold of that of wild-type RET ( For example, about 5-fold, about 7-fold, about 10-fold) (i.e., the compounds inhibited wild-type RET and (It was similarly potent against V804M and V804M). In some embodiments, another kinase Selectivity for wild-type or V804M RET kinase over ATP was demonstrated by enzyme assays ( For example, enzyme assays such as those provided herein. In embodiments, the compounds provided herein selectively induce cytotoxicity in RET mutant cells. Indicates harmfulness.

[0622] In some embodiments, the compounds provided herein are effective in the brain and / or central nervous system. exhibits CNS penetration. Such compounds cross the blood-brain barrier and enter the RE in the brain. T kinase and / or other CNS structures can be inhibited. In the present invention, the compounds provided herein are capable of crossing the blood-brain barrier in therapeutically effective amounts. For example, cancer (e.g., RET-associated cancers, such as RET-associated brain or CNS cancers) can be treated with Treatment of a patient with the condition may include administering (e.g., orally administering) a compound to the patient. In such embodiments, the compounds provided herein are useful in treating primary brain tumors or metastases. It is useful in treating brain tumors.

[0623] In some embodiments, a compound of formula I or a pharmaceutically acceptable salt thereof Solvates have been shown to have high GI absorption, low clearance, and low potential for drug-drug interactions. and one or more of the following:

[0624] The compounds of Formula I are useful in treating RET kinase inhibitors, such as RET-associated diseases and disorders. diseases and disorders that can cause cancer, such as proliferative disorders, including hematological cancers and solid tumors and gastrointestinal disorders such as IBS.

[0625] As used herein, the terms "treat" or "treatment" refer to curative or palliative Beneficial or desired clinical results include, but are not limited to, detectable or undetectable outcomes. Alleviation of all or part of the symptoms associated with a disease or disorder or condition, or reduction in the severity of the disease a stable state of disease (i.e., not worsening), a delay or slowing of disease progression, or a decrease in disease status Improvement or alleviation of a condition (e.g., one or more symptoms of a disease), and remission n) (whether in part or in whole) including, but not limited to, "Treatment " also means prolonging survival compared with expected survival without treatment. You can taste it.

[0626] As used herein, the terms "subject," "individual," or "patient" are used interchangeably. Used in mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, and pigs. It refers to any animal, including mammals such as mice, primates, and humans. In some embodiments, the patient is a human. is experiencing at least one symptom of the disease or disorder to be prevented, and / or In some embodiments, the subject is a patient receiving or receiving a treatment for a condition (e.g., a condition approved by a regulatory agency). as determined using a validated, e.g., FDA-approved, assay or kit The RET gene, the RET protein, or its expression or activity, or Identified or diagnosed as having cancer with dysregulation of any of the levels of RET (RET-associated cancer) In some embodiments, the subject is a patient who has been approved for the treatment of a disease (e.g., a condition approved by a regulatory agency). RET gene, RET protein (as determined using a specific assay or kit) dysregulation of the quality, or expression or activity, or any of the levels thereof The subject has a tumor that is positive for the HIV-1 virus. the RET gene, as determined using an assay or kit approved by the The level of RET protein, its expression or activity, or any of these The subject may have a tumor or tumors that are positive for nodal abnormalities. Use an agency-approved, e.g., FDA-approved, kit or assay. The tumor may be identified as having a gene encoding the RET gene, the RET protein, or a combination thereof. The subject may have a dysregulation of the expression or activity of, or any level of, In some embodiments, the subject is suspected of having a RET-associated cancer. In some embodiments, the subject is a patient who has a RET gene, RET protein, or a combination thereof. have a tumor with dysregulation of the expression or activity of and (optionally, the clinical records indicate that the subject has received the In some embodiments, the composition may be used to treat the patient. The patient is a pediatric patient.

[0627] As used herein, the term "pediatric patient" refers to a patient under the age of 21 at the time of diagnosis or treatment. The term "child" refers to patients in the following age groups: newborns (birth to 1 month after birth), infants (1 month after birth), to 2 years old), children (2 to 12 years old), adolescents (12 to 21 years old) The number of infected individuals can be divided into various subpopulations, including those born up to, but not including, the date of birth of the individual. Berhman RE, Kliegman R, Arvin AM, Nelson WE.Nelson Textbook of Pediatrics,15th E d.Philadelphia:WBSaunders Company,1996 , Rudolph AM,et al.Rudolph's Pediatrics,2 1st Ed. New York: McGraw-Hill, 2002, and Aver y MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. Several implementations In this condition, pediatric patients are those from birth to 28 days after birth, those from 29 days after birth to under 2 years of age, and those aged 2 years or older. From age 12 to under 12, or from age 12 to 21 (up to the 22nd birthday, but this In some embodiments, the pediatric patient is a pediatric patient from birth to 28 days after birth. From 29 days to under 1 year old, from 1 month to under 4 months old, from 3 months to under 7 months old, and 6 months old. Months to under 1 year old, 1 to under 2 years old, 2 to under 3 years old, 2 to under 7 years old, 3 to 5 years old Under 18, 5 to 10, 6 to 13, 10 to 15, or 15 Between the ages of 20 and 22.

[0628] In certain embodiments, compounds of formula I are useful in treating diseases and disorders as defined herein. The present invention is useful for preventing diseases such as autoimmune diseases, inflammatory diseases, and cancer. As used herein, the term "prevent" refers to preventing or preventing a disease or condition as described herein. Means preventing, in whole or in part, the onset, recurrence, or spread of a condition or its symptoms do.

[0629] As used herein, the term "RET-associated disease or disorder" refers to a disorder that is caused by a gene, RET kinase (also referred to herein as RET kinase protein), or (e.g., a RET gene, a RET kinase, a RET kinase domain, or a protein as described herein) Any of the types of dysregulation of expression or activity or level of any of those described Is it related to dysregulation of the expression, activity, or level of one or more of Non-limiting examples of RET-associated diseases or disorders include: Examples include cancer and gastrointestinal disorders such as irritable bowel syndrome (IBS).

[0630] As used herein, the term "RET-associated cancer" refers to a cancer that is caused by a gene involved in the RET gene, a RET kinase, or a protein involved in the RET kinase. ase (also referred to herein as RET kinase protein), or any of them It refers to cancers associated with or having dysregulated expression or activity or levels. Non-limiting examples of RET-associated cancers are described herein.

[0631] "RET gene, RET kinase, or the expression or activity of either thereof The phrase "dysregulated levels" refers to genetic mutations (e.g., resulting in the expression of a fusion protein) RET gene translocation, a mutation of at least one amino acid compared to the wild-type RET protein A deletion in the RET gene, resulting in expression of a RET protein containing the deletion, at one or more points Mutations in the RET gene that result in expression of a mutated RET protein, or is a change in the number of at least one amino acid in the RET protein compared to the wild-type RET protein. Alternative splicing of the RET mRNA resulting in a RET protein with a deletion ( alternatively spliced) version, or an excess of RET protein RET gene amplification leading to expression or the kinase domain of the RET protein in cells Pathogenicity of the activity of kinases (e.g., the constitutively active kinase domain of the RET protein) Caused by overexpression of the RET gene in cells leading to increased (pathogenic) Refers to autocrine activity. Another example is the activation of the RET gene, RET protein, or their The dysregulation of either expression or activity or level is constitutively active, or has increased activity compared to the protein encoded by a RET gene that does not contain the mutation The mutation may be in the RET gene encoding the RET protein having the following structure: The RET gene, the RET protein, or the expression or activity of either thereof Dysregulation of levels of the first part of RET, which contains a functional kinase domain, and partners Expression of a fusion protein containing a second portion of the protein (i.e., not RET) This can be the result of a genetic or chromosomal translocation, resulting in: , RET protein, or modulation of the expression or activity or level of any of them The abnormality may be the result of a genetic translocation between one RET gene and another non-RET gene. Non-limiting examples of proteins are listed in Table 1. RET kinase protein Non-limiting examples of mutations / insertions / deletions are listed in Table 2. RET kinase protein Further examples of mutations (e.g., point mutations) are RET inhibitor resistance mutations. Non-limiting examples of drug resistance mutations are listed in Tables 3 and 4.

[0632] The terms "wildtype" or "wild-type" , do not have a RET-associated disease, e.g., a RET-associated cancer (and optionally, do not have a RET-associated disease), are not at increased risk of developing and / or are suspected of having a RET-related disorder or not having a RET-associated disease, e.g., a RET-associated cancer. (and optionally, not being at increased risk of developing a RET-associated disease, and / or found in cells or tissues from subjects (not suspected of having a RET-associated disorder) , nucleic acids (e.g., RET gene or RET mRNA) or proteins (e.g., R ET protein).

[0633] The term "regulatory body" refers to the authority of a country to approve the medical use of a drug in that country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).

[0634] Methods of treating cancer (e.g., RET-associated cancer) in a patient in need of such treatment administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof or a solvate thereof, or a pharmaceutical composition thereof. For example, a method of treating a RET-associated cancer in a patient in need of such treatment. a) the RET gene, RET kinase, or any of them in a sample from a patient; b) detecting dysregulation of the expression or activity or level of Formula I; and or a pharmaceutically acceptable salt or solvate thereof, In some embodiments, a method is provided for the expression of a RET gene, a RET kinase, or a mutated RET gene. Dysregulation of the expression or activity or levels of any of the enzymes or enzymes Non-limiting examples of RET gene fusion proteins are listed in Table 1. In some embodiments, the fusion protein is KIF5B-RET. In some embodiments, the RET gene, RET kinase, or any of them Aberrant regulation of the expression or activity or level of one or more RET kinase proteins Includes point mutations / insertions in the RET kinase protein. Non-limiting examples are listed in Table 2. In some embodiments, the RET kinase The point mutations / insertion / deletions in the protein are M918T, M918V, C634W, and V8 In some embodiments, the compound of formula The compounds of I are i) Examples 1 to 20, ii) Examples 21 to 40, and iii) Examples 41 to 6 0, iv) Examples 61 to 80, v) Examples 81 to 100, vi) Examples 101 to 120, vii) Examples 121 to 140, viii) Examples 141 to 160, ix) Example 161 ~180, x) Examples 181-200, xi) Examples 201-220, xii) Example 2 21 to 240, xiii) Examples 241 to 260, xiv) Examples 261 to 280, xv ) Examples 281 to 300, xvi) Examples 301 to 320, xvii) Examples 321 to 323 40, xviii) Examples 341 to 360, xix) Examples 361 to 380, xx) Implementation Example Nos. 381 to 400, xxi) Example Nos. 401 to 420, xxii) Example Nos. 421 to 440, xxiii) Examples 441 to 460, xxiii) Examples 461 to 480, xx iv) Examples 481 to 500, xxv) Examples 501 to 520, xxvi) Example 521 xxvii) Examples 541 to 561, or It is a pharmaceutically acceptable salt or solvate.

[0635] In some embodiments of any of the methods or uses described herein, a cancer (e.g., RET-associated cancer) is a blood cancer. In some embodiments of either, the cancer (e.g., RET-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, Cancers (e.g., RET-associated cancers) include lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer, and ovarian cancer. Thyroid adenocarcinoma (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, recurrent thyroid carcinoma, if (intractable differentiated thyroid cancer), thyroid adenoma, endocrine gland tumor, lung adenocarcinoma, bronchiolopulmonary cell carcinoma, Multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), brown cell cyst, parathyroid hyperplasia, breast cancer, mammary cancer, mamm ary carcinoma), breast tumors, colorectal cancer (e.g., metastatic colorectal cancer), papillary renal cell carcinoma, gastrointestinal mucosal ganglioneuroma, inflammatory myofibroblastoma, or cervical cancer. In some embodiments of any of the methods or uses described herein, the method comprises administering to a patient a cancer (e.g., For example, RET-related cancers include acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AM), L), adolescent cancer, adrenocortical cancer, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma / rhabdoidoma tumors, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumor, Kitt's lymphoma, carcinoid tumor, cancer of unknown primary origin, cardiac tumor, cervical cancer, childhood cancer, notochord Leukemia, chronic lymphocytic leukemia (CML), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasia neoplasms, neoplasms by site, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, biliary Ductal carcinoma, ductal carcinoma in situ, embryonal tumor, endometrial carcinoma, ependymoma, esophageal carcinoma, nasal neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fallopian tube cancer, bone fibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST) ), germ cell tumor, gestational trophoblastic disease, glioma, hair cell tumor, hair cell leukemia, head and neck Neck cancer, thoracic neoplasms, head and neck neoplasms, CNS tumors, primary CNS tumors, cardiac cancer, hepatocellular carcinoma, Histiocytosis, Hodgkin's lymphoma, hypopharyngeal carcinoma, intraocular melanoma, pancreatic islet cell tumor, pancreatic intraneuronal tumor Secretory tumors, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, oral Lip cancer, liver cancer, lung cancer, lymphoma, macroglobulinemia, malignant fibrous histiocytoma of bone, osteocytes Cancer, melanoma, Merkel cell carcinoma, mesothelioma, metastatic squamous cell carcinoma, cervical cancer, midline carcinoma, oral cancer, multi- Multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myelodysplastic syndrome, myelodysplasia / bone Myeloproliferative neoplasms, Neoplasms by site, Neoplasms, Myeloid leukemia, Myeloid leukemia, Multiple myeloma, Myeloproliferative neoplasms, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma , non-small cell lung cancer, lung neoplasm, lung cancer, lung neoplasm (pulmonary neoplasm) , respiratory tract neoplasm, bronchial cancer, bronchial neoplasm, oral cancer, oral cavity cancer cancer), lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, Paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma tumor, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer , rectal cancer, colon cancer, colon cancer neoplasm, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer , sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue cancer, squamous cell carcinoma, squamous Epithelial neck cancer, gastric cancer, T-cell lymphoma, testicular cancer, pharyngeal cancer, thymoma thymic cancer, thyroid cancer, renal pelvic cancer and transitional cell carcinoma of the ureter, cancer of unknown primary, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and and Wilms' tumor.

[0636] In some embodiments, the hematological cancer (e.g., a hematological cancer that is a RET-associated cancer) is a leukemia cancer. disease, lymphoma (non-Hodgkin's lymphoma), Hodgkin's disease (also called Hodgkin's lymphoma), and myeloma, e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), Acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML) ML), chronic myeloid leukemia (CMML), chronic neutrophilic leukemia (CNL), acute undifferentiated leukemia Blood disease (AUL), anaplastic large cell lymphoma (ALCL), prolymphocytic leukemia (PML) , juvenile myelomonocytic leukemia (JMML), adult T-cell ALL, triple myelodysplasia (AML) AML with TMDS, mixed lineage leukemia (MLL), myelodysplastic syndrome (MDS) , myeloproliferative disorders (MPD), and multiple myeloma (MM). Further examples of hematological cancers include polycythemia vera (PV), essential thrombocytopenia (ET), and myeloproliferative disorders (MPs) such as idiopathic primary myelofibrosis (IMF / IPF / PMF). In one embodiment, the hematological cancer (e.g., a hematological cancer that is a RET-associated cancer) is , AML or CMML.

[0637] In some embodiments, the cancer (e.g., a RET-associated cancer) is a solid tumor. Examples of tumors (e.g., solid tumors that are RET-associated cancers) include, for example, thyroid cancer (e.g., thyroid carcinoma) and papillary adenocarcinoma, medullary thyroid carcinoma), lung cancer (e.g., lung adenocarcinoma, small cell lung carcinoma), pancreatic cancer, pancreatic ductal carcinoma, breast Cancer, colon cancer, colorectal cancer, prostate cancer, renal cell carcinoma, head and neck tumors, neuroblastoma, and melanoma For example, Nature Reviews Cancer, 2014, 14 , 173-186.

[0638] In some embodiments, the cancer is lung cancer, papillary thyroid cancer, differentiated thyroid cancer, recurrent thyroid cancer, or thyroid adenocarcinoma, refractory differentiated thyroid cancer, and multiple endocrine neoplasia type 2A or 2B (ME, respectively). N2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary nephropathy The cancer is selected from the group consisting of gastrointestinal mucosal ganglioneuroma, gastrointestinal mucosal ganglioneuroma, and cervical cancer.

[0639] In some embodiments, the patient is a human.

[0640] The compounds of Formula I and pharmaceutically acceptable salts and solvates thereof are also useful in treating RET-associated cancers. It is also useful for treating

[0641] Thus, RET-associated cancers, such as any of the exemplary RET-associated cancers disclosed herein, 20. A method for treating a patient diagnosed or identified with any of the following, comprising administering to the patient a therapeutically effective amount of or a pharmaceutically acceptable salt or solvate thereof, Also provided herein are methods that include administering the product, or a pharmaceutical composition thereof.

[0642] Expression of RET kinase, RET gene, or any (e.g., one or more) thereof Alternatively, dysregulation of the activity or level of RET kinase may contribute to tumorigenesis. Modulation of expression or activity or levels of the enzyme, RET gene, or any of them The abnormality may be a translocation or overexpression of the RET kinase, the RET gene, or the RET kinase domain. The translocation may be a translocation involving the RET kinase domain. and the mutation may comprise a mutation comprising a RET ligand binding site, and the amplification may comprise a mutation comprising a RET gene Other dysregulations may be due to RET mRNA splice variants and RE T autocrine / paracrine signaling may also contribute to tumorigenesis.

[0643] In some embodiments, the RET gene, the RET kinase, or both thereof Dysregulation of the expression, activity or level of RET kinase is due to overexpression of wild-type RET kinase ( In some embodiments, the RET gene is a cytoplasmic ... a RET kinase protein, or the expression or activity or reactivity of any of them Dysregulation of the bell may indicate, for example, the kinase domain portion or kinase activity. overexpression in a chromosomal segment containing the RET gene or a portion thereof, including a portion that can , activation, amplification, or mutation.

[0644] In some embodiments, the RET gene, the RET kinase protein, or Aberrant regulation of the expression, activity, or level of any of these genes results in a RET gene fusion. In some embodiments, the RET gene is a chromosomal translocation or inversion. a RET kinase protein, or the expression or activity or reactivity of any of them Dysregulation of RET is due to the fact that expressed proteins contain residues from non-RET partner proteins. a fusion protein containing a minimal functional RET kinase domain, This is the result of the seat.

[0645] Non-limiting examples of RET fusion proteins are shown in Table 1.

[0646] [Table 1-1] [Table 1-2] [Table 1-3]

[0647] In some embodiments, the RET gene, the RET kinase, or both thereof The dysregulation of expression or activity or level of one or more of the RET kinases This includes deletions (e.g., deletion of the amino acid at position 4), insertions, or point mutation(s). In some embodiments, the RET gene, the RET kinase, or either thereof Dysregulation of expression, activity, or levels of the RET kinase domain results in constitutive activity. The deletion of one or more residues from RET kinase results in the

[0648] In some embodiments, the RET gene, the RET kinase, or both thereof Aberrant regulation of the expression or activity or level of RET kinase, as compared to wild-type RET kinase, resulting in the production of RET kinases having one or more amino acid substitutions, insertions, or deletions. , containing at least one point mutation in the RET gene (e.g., those listed in Table 2 (See point mutation).

[0649] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6]

[0650] In some embodiments, the RET gene, the RET kinase, or both thereof Aberrant regulation of the expression or activity or level of RET kinase, as compared to wild-type RET kinase, resulting in the production of RET kinases having one or more amino acid substitutions, insertions, or deletions. , including at least one point mutation in the RET gene (e.g., those listed in Table 2a). (See point mutations.)

[0651] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4]

[0652] In some embodiments, the RET gene, the RET kinase, or both thereof Dysregulation of the expression, activity, or level of RET mRNA is due to splicing. The RET kinase domain contains a mutation that results in constitutive activity (wild-type RET). Selective sequence of RET with at least one deleted residue (compared to the ET protein) This results in the expressed protein being a spliced ​​variant.

[0653] As defined herein, a "RET kinase inhibitor" is any compound that exhibits RET inhibitory activity. In some embodiments, the RET kinase inhibitor is a compound that inhibits RET kinase. Exemplary RET kinase inhibitors are selective for the RET kinase activity measured in the assays described herein. If so, it is less than about 1000 nM, less than about 500 nM, less than about 200 nM, less than about 100 nM less than about 50 nM, less than about 25 nM, less than about 10 nM, or less than about 1 nM RET kinase activity Inhibitory activity against enzymes (IC 50 In some embodiments, RET The kinase inhibitor has a potency of less than about 25 nM, about Inhibitory activity against RET kinase of less than 10 nM, less than about 5 nM, or less than about 1 nM ( I C 50 ) can be shown.

[0654] As used herein, a "first RET kinase inhibitor" or "first RET inhibitor" refers to a compound that inhibits RET kinase activity. " is a RET kinase inhibitor as defined herein, but is a compound of formula I as defined herein. or a pharmaceutically acceptable salt or solvate thereof. A "second RET kinase inhibitor" or "second RET inhibitor" as used herein is defined as RET kinase inhibitors as defined herein, but comprising a compound of formula I or a compound thereof as defined herein. The present invention does not include pharmaceutically acceptable salts or solvates of the first and second RET inhibitors. When both are present in the methods provided herein, the first and second RET kinase inhibitors The agents are different.

[0655] In some embodiments, the RET gene, the RET kinase, or both thereof Aberrant regulation of the expression or activity or level of RET kinase, as compared to wild-type RET kinase, RET kinases with one or more amino acid insertions or deletions, RET kinase with one or more amino acid substitutions, insertions or deletions in the gene Optionally, the RET gene contains at least one point mutation that results in the production of Therefore, the resulting RET kinase may be either wild-type RET kinase or a mutant containing the same mutation. and one or more first RET kinase inhibitor(s) compared to a RET kinase that does not Such mutations are more resistant to inhibition of their phosphotransferase activity by optionally, by treatment with a compound of formula I or a pharmaceutically acceptable salt or solvate thereof. does not reduce the sensitivity of cancer cells or tumors that have RET kinase to treatment (e.g., (compared to cancer cells or tumors that do not contain the specific RET inhibitor resistance mutation). In this form, the RET inhibitor-resistant mutations are expressed in wild-type RET kinase or the same first RET The first RET kinase is expressed in the presence of a kinase inhibitor, compared to a RET kinase that does not have the same mutation. In the presence of kinase inhibitors, V max Increase in ATP K m Decrease in K of RET kinase inhibitors of 1 D and a RET kinase having one or more of the following increases: It is possible.

[0656] In another embodiment, the RET gene, RET kinase, or expression of either thereof Dysregulation of expression, activity, or levels of RET kinase in one or more This results in the production of a RET kinase having the above amino acid substitutions, and the wild-type RET kinase or or a RET kinase not containing the same mutation, A small mutation in the RET gene that results in increased tolerance to naturally tolerated salts or solvates. In such embodiments, the RET inhibitor-resistant mutation is a wild-type RET kinase or a compound of Formula I or a pharmaceutically acceptable salt thereof The compound of formula I or In the presence of a pharmaceutically acceptable salt or solvate thereof, V max Increase in K m Decrease in and K. DThis can result in a RET kinase having one or more of the following reductions:

[0657] Examples of RET inhibitor resistance mutations include, for example, gatekeeper residues, P-loop residues, DFG Residues in and near the motif and the ATP cleft solvent front amino acid residues are included. These include, but are not limited to, the ATP binding site in the tertiary structure of RET kinase and These types of mutations may include point mutations, insertions, or deletions in and near the nucleotide sequence. Examples include residues in the activation loop, residues near or interacting with the activation loop, Enzyme residues, including but not limited to, residues that contribute to the active or inactive enzyme conformation Changes in residues that may affect activity and / or drug binding, proceeding through the C-helix These include alterations including mutations, deletions, and insertions within the loops and C helix. The specific residues or residue regions that are mutated (RET inhibitor-resistant mutations) are These include, but are not limited to, those listed in Table 3 based on the protein sequence (e.g., SEQ ID NO: 1). Further examples of RET inhibitor-resistant mutation positions are shown in Table 4. These residues are not limited to: Changes to the sequence can include single or multiple amino acid changes, insertions within or adjacent to the sequence, and and deletions within or adjacent to the sequence.

[0658] Exemplary sequence of the mature human RET protein (SEQ ID NO: 1) MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYW EKL YVDQAAGTPL LYVHALRDAP EEVPSFRLGQ HLY GTYRTRL HENNWICIQE DTGLLYLNRS LDHSSWEKLS VRNRGFPLLT VYLKVFLSPT SLREGECQWP GCARVY FSFF NTSFPACSSL KPRELCFPET RPSFRIRENR PP GTFHQFRL LPVQFLCPNI SVAYRLLEGE GLPFRCAPD S LEVSTRWALD REQREKYELV AVCTVHAGAR EEVVM VPFPV TVYDEDDSAP TFPAGVDTAS AVVEFKRKED T VVATLRVFD ADVVPASGEL VRRYTSTLLP GDTWAQQT FR VEHWPNETSV QANGSFVRAT VHDYRLVLNR NLSISENRTM QLAVLVNDSD FQGPGAG VLL LHFNVSVLPV SLHLPSTYSL SVSRRARRFA QIG KVCVENC QAFSGINVQY KLHSSGANCS TLGVVTSAED TSGILFVNDT KALRRPKCAE LHYMVVATDQ QTSRQA QAQL LVTVEGSYVA EEAGCPLSCA VSKRRLECEE CG GLGSPTGR CEWRQGDGKG ITRNFSTCSP STKTCPDGH C DVVETQDINI CPQDCLRGSI VGGGHEPGEPR GIKAG YGTCN CFPEEEKCFC EPEDIQDPLC DELCRTVIAA A VLFSFIVSV LLSAFCIHCY HKFAHKPPIS SAEMTFRR PA QAFPVSYSSS GARRPSLDSM ENQVSVDAFK ILEDPKWEFP RKNLVLGKTL GEGEFGK VVK ATAFHLKGRA GYTTVAVKML KENASPSELR DLL SEFNVLK QVNHPHVIKL YGACSQDGPL LLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNSSSLDH PDERAL TMGD LISFAWQISQ GMQYLAEMKL VHRDLAARNI LV AEGRKMKI SDFGLSRDVY EEDSYVKRSQ GRIPVKWMA I ESLFDHIYTT QSDVWSFGVL LWEIVTLGGN PYPGI PPERL FNLLKTGHRM ERPDNCSEEM YRLMLQCWKQ E PDKRPVFAD ISKDLEKMMV KRRDYLDLAA STPSDSLI YD DGLSEEETPL VDCNNAPLPR ALPSTWIENK LYGMSDPNWP GESPVPLTRA DGTNTGF PRY PNDSVYANWM LSPSAAKLMD TFDS

[0659] In some embodiments, compounds of Formula I and pharmaceutically acceptable salts and solvents The compound may be administered in combination with or in combination with existing drug therapy (e.g., other RE). a first and / or second RET kinase inhibitor) or as follow-up therapy for a RET inhibitor-resistant mutation (e.g., after the first RET inhibitor) increased resistance to, for example, amino acid position 804, e.g., V804M, V804L, or V804E, and / or one or more RETs listed in Tables 3 and 4 These compounds are useful in treating patients who develop cancers with mutations in their genomic DNA that result in inhibitor-resistant mutations. The first and second RET kinase inhibitors are described herein. In this embodiment, the first or second RET kinase inhibitor is cabozantinib, vandetanib , alectinib, sorafenib, lenvatinib, ponatinib, dovitinib, sunitinib, Foretinib, BLU667, and BLU6864. do.

[0660] In some embodiments, a compound of Formula I or a pharmaceutically acceptable salt thereof and a solution thereof The mediator may be (e.g., increased resistance to the first and second RET inhibitors, e.g., amino resulting in a substitution at acid position 804, e.g., V804M, V804L, or V804E. (i) are useful for treating cancers identified as having one or more RET inhibitor resistance mutations. Non-limiting examples of RET inhibitor resistance mutations are listed in Tables 3 and 4. [Table 4] [Table 5]

[0661] The oncogenic role of RET initially arises from thyroid follicular cells and is responsible for the most common thyroid malignancies. It has been described in the tumor papillary thyroid carcinoma (PTC) (Grieco et al., Cell, 1990, 60, 557-63). Approximately 20-30% of PTCs are promoter- and the RET tyrosine kinase domain (Greco et al., QJNucl. Med. Mol. Imaging, 2009, 53, 440-54) Somatic chromosomal rearrangements (translocations or inversions) linking a constitutively expressed 5' segment This rearrangement promotes its ectopic expression in thyroid cells. The fusion protein thus produced is referred to as a "RET / PTC" protein. RET / PTC1 is a fusion of CCDD6 and RET that is commonly seen in papillary thyroid carcinoma. Similarly, both RET / PTC3 and RET / PTC4 are commonly found in papillary thyroid carcinoma. The fusion of ELE1 and RET is known to occur in the RET / PTC3 and RET / PTC4 genes. Fusion events resulting in different proteins with different molecular weights (e.g., F ugazzola et al., Oncogene, 13(5):1093-7,19 96). Some RET fusions associated with PTC are called "RET / PTC" Instead, they are referred to as fusion proteins themselves. For example, RET and E Fusions between both LKS and PCM1 are found in PTCs, but the fusion proteins These are referred to as ELKS-RET and PCM1-RET (see, e.g., Romei and E lisei,Front.Endocrinol.(Lausanne),3:54,d oi:10.3389 / fendo.2012.00054,2012). The role of RET-PTC rearrangements in the pathogenesis of PTC has been investigated in transgenic mice. It has been confirmed that To date, various fusion partners have been identified in PTC and other cancer types. have been identified, all of which exhibit ligand-independent RET dimerization and constitutive kinase activity (See, e.g., Table 1) Recently, the 10.6 Mb pericycle of chromosome 10, where the RET gene is mapped, was identified. Intrinsic inversions have been identified in approximately 2% of patients with lung adenocarcinoma, and the chimeric gene KIF5B -resulting in different variants of RET (Ju et al., Genome Res., 2012,22,436-45,Kohno et al.,2012,Nature Med.,18,375-7, Takeuchi et al.,Nature Med .,2012,18,378-81, Lipson et al.,2012,Natu re Med., 18, 382-4). The fusion transcript was highly expressed, and the resulting chimeric All of the proteins contain the N-terminal coiled-coil region of KIF5B, which mediates homodimerization. The RET kinase domain is comprised of the terminal portion and the entire RET kinase domain. do not have oncogenic alterations (EGFR or K-Ras mutations, ALK translocations, etc.), which is These findings suggest that IF5B-RET fusion may be a driver mutation in lung adenocarcinoma. The oncogenic potential of F5B-RET was confirmed by transfecting a fusion gene into cultured cell lines. This has been confirmed by the RET-PTC fusion protein, as well as by KIF5B-RET is constitutively phosphorylated and induces transformation of NIH-3T3 and IL- However, the CCDC6-RET fusion induces independent proliferation of BA-F3 cells. Other RET fusion proteins, such as the IL-11 protein, have been identified in patients with lung adenocarcinoma, has been found to play an important role in the proliferation of the human lung adenocarcinoma cell line LC-2 / ad. (Journal of Thoracic Oncology, 2012, 7(1 2):1872-1876). RET inhibitors are useful in the treatment of lung cancers containing RET rearrangements. It has been shown that (Drilon, AE et al. J Clin Onco l 33, 2015(suppl;abstr 8007)). RET fusion proteins It has also been identified in patients with colorectal cancer (Song Eun-Kee, e International Journal of Cancer,201 5,136:1967-1975).

[0662] Medullary thyroid carcinoma arising from parafollicular calcitonin-producing cells with RET sequence rearrangement Gain-of-function point mutations in the RET proto-oncogene also contribute to oncogenic events, as shown in (MTC). (de Groot, et al., Endocrine Rev., 200 6,27,535-60,Wells and Santoro,Clin.Cance r Res.,2009,15,7119-7122). Approximately 25% of MTC cases are due to RET. A gene affecting neuroendocrine organs caused by a germline activating point mutation It is associated with multiple endocrine neoplasia type 2 (MEN2), a group of inherited cancer syndromes. In subtypes (MEN2A, MEN2B, and familial MTC / FMTC), RE T gene mutations are strongly phenotypic and genetically conserved, determining different MTC aggressiveness and clinical manifestations of the disease. In MEN2A syndrome, mutations occur in the cysteine-rich extracellular It contains one of six cysteine ​​residues (mainly C634) located in the region, which is ligand-independent. This leads to dependent homodimerization and constitutive RET activation. Patients present at a young age (5-25 years). MTC develops in patients with pheochromocytoma (50%) and hyperparathyroidism. MEN2B is primarily caused by the M918T mutation located within the kinase domain. This mutation constitutively activates RET in its monomeric state, Alters substrate recognition by kinases. MEN2B syndrome is characterized by early onset (<1 year). and by highly aggressive forms of MTC, pheochromocytoma (50% of patients) and ganglioneuroma. In FMTC, the only disease manifestation is MT, which usually occurs in adulthood. C. Many different mutations have been detected throughout the RET gene. The remaining 75% of cases are sporadic, and approximately 50% of those have RET somatic mutations. The most frequent mutation is M918, which is associated with the most aggressive phenotype, similar to MEN2B. Somatic point mutations in RET are also associated with colorectal cancer (Wood et al., 2004). Science, 2007, 318, 1108-13) and small cell lung cancer (Jpn.JC Cancer Res., 1995, 86, 1127-30) It is written.

[0663] RET signaling elements are expressed in primary breast tumors and in breast tumor cell lines. It has been found to functionally interact with the estrogen receptor-cc pathway (Bo ulay et al.,Cancer Res.2008,68,3743-51,P laza-Menacho et al.,Oncogene,2010,29,464 8-57), RET expression and activation by GDNF family ligands are regulated in different species. may play an important role in perineural invasion by cancer cells (Ito et al. .,Surgery,2005,138,788-94,Gil et al.,JN atl.Cancer Inst.,2010,102,107-18, Iwahash i et al., Cancer, 2002, 94, 167-74).

[0664] RET is also expressed in 30-70% of invasive breast cancers, and its expression is regulated by estrogen. It is relatively more frequent in receptor-positive tumors (Plaza-Menacho, I., e t al., Oncogene, 2010, 29, 4648-4657, Esseghi r,S.,et al.,Cancer Res.,2007,67,11732-11 741, Morandi, A., et al., Cancer Res., 2013, 7 3,3783-3795,Gattelli,A.,EMBO Mol.Med.,20 13,5,1335-1350).

[0665] Identification of RET rearrangements was confirmed in PDXs established from colorectal cancer (patient-derived xenografts). The frequency of such events in patients with colorectal cancer remains unknown. Although not specifically defined, these data support the use of RE as a target in this indication. suggesting a role for T (Gozgit et al., AACR Annual Meeting eting 2014). Studies have shown that the RET promoter is frequently methylated in colorectal cancer. Heterozygous missense mutations predicted to reduce RET expression are present in 5–10% of cases. This indicates that RET has been identified in sporadic colon cancers. suggest that it may have some properties of a suppressor gene (Luo, Y., et al .,Oncogene,2013,32,2037-2047,Sjoblom,T., et al.,Science,2006,268-274,Cancer Genom e Atlas Network,Nature,2012,487,330-337) .

[0666] An increasing number of tumor types now have significant levels of risk factors that can influence tumor progression and spread. It has been shown that RET is expressed in 50-65% of pancreatic tumors. It is expressed in ductal carcinomas, and expression is more frequent in metastatic and higher-grade tumors. (Ito, Y, et al., Surgery, 2005, 138, 788-794, Zeng,Q.,et al.,J.Int.Med.Res.2008,36,656 -664).

[0667] In hematopoietic neoplasms, RET is involved in acute myeloid leukemia (AML) with monocytic differentiation, and CMML (Gattei, V. et al., Blood, 1997,89,2925-2937,Gattei,V.,et al.,Ann.H ematol,1998,77,207-210, Camos, M., Cancer R es.2006,66,6947-6954). Recent studies have shown that chronic myelomonocytic leukemia A rare chromosomal rearrangement involving RET has been identified in patients with CMML. CMML is often associated with rearrangements of several tyrosine kinases, which This results in the expression of a chimeric cytoplasmic oncoprotein that leads to activation of the RAS pathway (Kohlm ann,A.,et al.,J.Clin.Oncol.2010,28,2858- In the case of RET, gene fusions linking RET to BCR (BCR-RET) or or fibroblast growth factor receptor 1 oncogene partner-binding gene fusion (FGFR1 OP-RET) is transforming in early hematopoietic progenitor cells and mediates the maturation of these cells. are diverted towards the monocyte pathway, presumably by the initiation of RET-mediated RAS signaling. (Ballerini, P., et al., Leukemia, 2012, 26 ,2384-2389).

[0668] RET expression is also found in various cancers, including prostate cancer, small cell lung cancer, melanoma, renal cell carcinoma, and head and neck tumors. It has also been shown to occur in several other tumor types (Narita, N., et al., t al., Oncogene, 2009, 28, 3058-3068, Mulliga n,LM,et al.,Genes Chromosomes Cancer,1 998,21,326-332,Flavin,R.,et al.,Urol.Onc. ol.,2012,30,900-905, Dawson,DM,J Natl C ancer Inst, 1998, 90, 519-523).

[0669] In neuroblastoma, RET expression and activation by GFLs is related to other neurotrophic factor receptors. downregulating N-Myc, potentially in cooperation with NF-κB, which plays a role in tumor cell differentiation and its development. Currently, it is a marker of poor prognosis (Hofstra, RM, W., et al., Hu m.Genet.1996,97,362-364,Petersen,S.andB ogenmann, E., Oncogene, 2004, 23, 213-225, Bro. deur,GM,Nature Ref.Cancer,2003,3,203-2 16).

[0670] Multi-targeted inhibitors that cross-react with RET are known (Borrello, MG, e t al.,Expert Opin.Ther.Targets,2013,17(4 ), 403-419, International Patent Publication WO2014 / 141187, WO2014 / 184 069, and WO2015 / 079251).

[0671] Thus, a patient may be administered a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. a patient diagnosed with (or suspected of having) cancer, comprising administering a compound or solvate thereof Provided herein are methods for treating a patient (as defined herein) comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, and administering to a patient identified or diagnosed with a RET-associated cancer the Methods are also provided herein. In some embodiments, a patient or a patient or in any of the non-limiting examples of assays described herein. By carrying out the above, the RET gene, the RET kinase, or any of them regulatory agencies to identify dysregulation of expression or activity or levels of A test or assay approved, e.g., FDA-approved, for RET-associated cancer In some embodiments, the test or assay In some embodiments, the cancer is a RET-associated cancer. For example, a RET-associated cancer can be a cancer that contains one or more RET inhibitor-resistant mutations.

[0672] A method for treating cancer in a patient in need thereof, comprising: (a) administering to the patient (b) determining whether the cancer is a RET-associated cancer; and If determined, the patient is administered a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. or a solvate thereof, or a pharmaceutical composition thereof. Some embodiments of these methods involve administering to the subject another anti-cancer agent (e.g., a second RE). a T inhibitor, a second compound of formula I or a pharmaceutically acceptable salt or solvate thereof, and In some embodiments, the subject further comprises administering a first have been previously treated with a RET inhibitor or have received other anti-cancer treatment, e.g., tumor resection In some embodiments, the patient has been previously treated with radiation therapy or radiation therapy. or in a biopsy sample from the patient, or in a non-limiting example of the assays described herein. By carrying out any of the above examples, the RET gene, RET kinase, or a regulatory protein for identifying dysregulation of the expression or activity or level of any of RET-related markers using an agency-approved, e.g., FDA-approved, test or assay In some embodiments, the test or assay is performed using a kit. In some embodiments, the cancer is a RET-associated cancer. , a RET-associated cancer can be a cancer that contains one or more RET inhibitor-resistant mutations.

[0673] The patient has a mutation in the RET gene, RET kinase, or the expression or activity of either of them. or dysregulation of the levels of conducting an assay and administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof; The RET gene, RET kinase, or a salt or solvate thereof, or a pharmaceutical composition thereof, or a dysregulation of the expression, activity or level of any of them. and administering (e.g., specifically or selectively administering) the compound to a patient. Also provided are methods for treating rheumatoid arthritis. Some embodiments of these methods involve administering to a subject another an anti-cancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharmaceutically acceptable salt thereof); These methods further include administering a therapeutically effective amount of a compound selected from the group consisting of a compound of formula (I), a salt or solvate thereof, or immunotherapy. In some embodiments, the subject has been previously treated with a first RET inhibitor or or have been previously treated with another anti-cancer therapy, such as tumor resection or radiation therapy. In some embodiments, the patient is a patient suspected of having a RET-associated cancer, Patients who present with one or more symptoms of a related cancer or who are at high risk of developing a RET-related cancer In some embodiments, the assay is performed using next generation sequencing, pyrolysis, or Some embodiments utilize sequencing, immunohistochemistry, or degradative FISH analysis. In the present study, the assay is a regulatory agency approved assay, e.g., an FDA approved assay. Further non-limiting assays that can be used in these methods are described herein. Further assays are also known in the art. In some embodiments, the RET gene, the RET kinase, or the expression of either thereof is The dysregulation of expression or activity or level includes one or more RET inhibitor resistance mutations.

[0674] The RET gene, RET kinase, or the expression or activity of either of them The presence of dysregulated levels identifies a patient as having a RET-associated cancer, and gene, RET kinase, or the expression or activity or level of any of them To determine whether a patient has dysregulation, an assay ( A subject is identified as having a RET-associated cancer through performing an in vitro assay (e.g., an in vitro assay). 2. A compound of formula I or a pharmaceutical composition thereof for use in treating a RET-associated cancer in a patient diagnosed or being treated for the treatment of a RET-associated cancer. Also provided are physiologically acceptable salts or solvates or pharmaceutical compositions thereof. T gene, RET kinase, or the expression or activity or level of any of them The presence of dysregulation of the RET gene identifies a patient as having a RET-associated cancer. , RET kinase, or dysregulation of the expression or activity or level of any of them An assay is performed on a sample obtained from a patient to determine whether the patient has a mutation. RET-associated cancer in patients identified or diagnosed with RET-associated cancer through the steps 1. The use of a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer. The use of a salt or solvate thereof is also provided. Some embodiments of any of these include, but are not limited to, those in which the patient has a gene encoding the RET gene, RET kinase, or a gene encoding a RET kinase. It has been determined that the expression, activity, or level of any of these is abnormally regulated. and recording the assessment result in a clinical record (e.g., a computer readable medium) of the patient. Through the practice of the present invention, a compound of formula I or a pharmaceutically acceptable salt or solvate thereof, In some embodiments, the assay comprises administering a pharmaceutical composition thereof to a subject. , next-generation sequencing, pyrosequencing, immunohistochemistry, or degradative FISH In some embodiments, the assay is approved by a regulatory agency. In some embodiments, the RE T gene, RET kinase, or the expression or activity or level of any of them The dysregulation of RET comprises one or more RET inhibitor resistance mutations.

[0675] In patients in need of treatment or identified or diagnosed with RET-associated cancer 1. A compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of cancer in Solvates are also provided. In patients identified or diagnosed with RET-associated cancer and administering to a subject a compound of formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating cancer. Use of salts or solvates is also provided. In some embodiments, the cancer is RET-associated cancers, such as RET-associated cancers with one or more RET inhibitor resistance mutations. In some embodiments, the patient has a RET gene in a biopsy sample from the patient or the sample. gene, RET kinase, or the expression or activity or reactivity of any of them. Regulatory approved, e.g., FDA-approved, to identify bell dysregulation and have been identified or diagnosed as having a RET-associated cancer using the kit. As used herein, RET-associated cancers include those described herein and known in the art. .

[0676] In some embodiments of any of the methods or uses described herein, the patient is The RET gene, RET kinase, or the expression or activity or level of either thereof The subject has been identified or diagnosed with cancer having dysregulation of the bell. In some embodiments of any of the or the uses, the patient has a RET gene, a RET kinase enzymes, or dysregulation of the expression or activity or levels of any of them Any of the methods or uses described herein have a tumor that is positive. In one embodiment, the patient has a defect in the RET gene, RET kinase, or either thereof. have tumor(s) positive for dysregulation of expression or activity or level of In some embodiments of any of the methods or uses described herein, In this form, the patient is diagnosed with a tumor that is defective in the RET gene, RET kinase, or either of these. The patient may have a dysregulation of the expression or activity or level of In some embodiments of any of the methods or uses, the patient has a RET-associated cancer (e.g., For example, cancer with one or more RET inhibitor resistance mutations. In one embodiment, the method comprises treating a RET-associated cancer in a patient in need of such treatment. The method comprises: a) detecting the RET gene, RET kinase, or a combination thereof in a sample from a patient; detecting dysregulation of either expression or activity or level; b) a therapeutically effective amount or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the RET gene, RE T kinase, or any of them, dysregulation of expression or activity or levels The RET gene fusion proteins include one or more fusion proteins. Non-limiting examples of RET gene fusion proteins are listed in Table 1. In some embodiments, the fusion protein is a KIF5B-RE In some embodiments, the RET gene, RET kinase, or Aberrant regulation of the expression or activity or level of one or more RET kinases Includes point mutations / insertions / deletions in the protein. RET kinase protein point mutations / insertions / deletions Non-limiting examples of insertions / deletions are listed in Table 2. In some embodiments, R The point mutations / insertions / deletions in the ET kinase protein are M918T, M918V, C63 In some embodiments, the ion exchange membrane is selected from the group consisting of V804W, V804L, and V804M. In the present invention, the RET gene, the RET kinase, or the expression or activity of either of them is also The dysregulation of RET levels may include one or more RET inhibitor resistance mutations. Non-limiting examples of mutations are described in Tables 3 and 4. In some embodiments, The RET inhibitor resistance mutation is V804M. In some embodiments, the RET gene Modulation of expression or activity or levels of a protein, a RET kinase, or any of them The cancers having the abnormality may be detected by a regulatory agency approved, e.g., FDA approved, assay or is determined using a kit. In some embodiments, the RET gene, RETkinase Positive for dysregulation of the expression, activity, or levels of any of these enzymes A tumor that is resistant to RET inhibitors is one that is positive for one or more RET inhibitor resistance mutations. In some embodiments, the RET gene, the RET kinase, or the expression of either thereof is Tumors with dysregulated expression or activity or levels of steroids approved by regulatory authorities For example, it may be determined using an FDA-approved assay or kit.

[0677] In some embodiments of any of the methods or uses described herein, the patient The present inventors have found that a patient has a mutation in the RET gene, RET kinase, or the expression or activity of either of them. Tumors with dysregulation of the gene or level (e.g., one or more RET inhibitor resistance mutations) In some embodiments, the patient has clinical documentation showing that the patient has a tumor. The record may include a patient receiving a compound of formula I or a pharmaceutically acceptable salt or solvate thereof; indicates that the patient should be treated with one or more of the compositions provided herein. In some embodiments, the RET gene, the RET kinase, or the expression of either thereof is Cancers with dysregulated expression, activity, or levels of RET are characterized by one or more RET inhibitor-resistant mutations. In some embodiments, the cancer is a cancer having a mutation in the RET gene, RET kinase, or Cancers with dysregulation of the expression or activity or levels of any of these Determined using an assay or kit approved by an authority, e.g., FDA-approved In some embodiments, the RET gene, RET kinase, or any of them Tumors positive for dysregulation of expression or activity or level of one or more In some embodiments, the tumor is positive for a RET inhibitor resistance mutation listed above. , the RET gene, the RET kinase, or the expression or activity of any of them Tumors with dysregulated levels of a regulatory approved, e.g., FDA approved, , determined using an assay or kit.

[0678] A method of treating a patient comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The RET gene, RET kinase, or a salt or solvate thereof is administered to a patient. Clinical records showing dysregulation of any expression, activity, or level Also provided are methods for treating a patient having a RET gene, comprising administering to said patient a gene encoding the RET gene, T kinase, or dysregulation of the expression or activity or levels of any of them. Manufacture of a medicament for treating RET-associated cancer in a patient with clinical records indicating The use ...

Claims

1. A compound of formula I, 【Chemistry 1】 and a method for preparing pharmaceutically acceptable salts and solvates thereof, comprising: During the ceremony, X １ , X ２ , X ３ , and X ４ are independently CH, CF, CCH ３ , or N, and X １ , X ２ , X ３ , and X ４ is N; A is CN, B, (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro; (c) hydroxyC2-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro or C3-C6 cycloalkylidene rings; (d) dihydroxyC3-C6 alkyl-, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring; (e) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1 to 3 fluoro; (f) (R １ R ２ N) C1-C6 alkyl-, wherein said alkyl moiety is optionally substituted with OH; R １ and R ２ are independently H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), (R １ R ２ N) C1-C6 alkyl-, (g) hetAr １ C1-C3 alkyl-, where hetAr １ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O, and S, and hetAr １ is optionally substituted with one or more independently selected C1-C6 alkyl substituents, １ C1-C3 alkyl-, (h) (C3-C6 cycloalkyl)C1-C3 alkyl-, wherein said cycloalkyl is optionally substituted with OH; (i) (hetCyc ａ ) C1-C3 alkyl-, (j)hetCyc ａ -、 (k) C3-C6 cycloalkyl-, wherein said cycloalkyl is optionally substituted with OH; (l) (C1-C4 alkyl)C(=O)O-C1-C6 alkyl-, wherein said C1-C4 alkyl moiety and C1-C6 alkyl moiety are each optionally and independently substituted with 1 to 3 fluoro; or (m) (R １ R ２ N) C(=O)C1-C6 alkyl-, where R １ and R ２ are independently H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), (R １ R ２ N) C(=O)C1-C6 alkyl-; hetCyc ａ - is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, and is optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoro), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, (C1-C6 alkyl)C(═O)—, (C1-C6 alkoxy)C1-C6 alkyl-, and fluoro; or hetCyc ａ is substituted with oxo, Ring D is (i) a saturated 4- to 7-membered heterocyclic ring having two ring nitrogen atoms; (ii) a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and, optionally, a third ring heteroatom that is oxygen; (iii) a saturated 7- to 11-membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9- to 10-membered bicyclic fused heterocyclic ring having two ring nitrogen atoms; Each of said rings is (a) 1 to 4 groups independently selected from halogen, OH, or C1-C3 alkyl optionally substituted with 1 to 3 fluoro, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro; (b) a C3-C6 cycloalkylidene ring, or (c) oxo group is optionally replaced by E, (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro; (c) (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with 1 to 3 fluoro; (d) (C1-C6 alkyl)C(=O)-, wherein the alkyl portion is 1 to 3 fluoro or R ｇ R ｈ N-substituent (wherein R ｇ and R ｈ are independently H or C1-C6 alkyl; (e) (hydroxyC2-C6 alkyl)C(=O)- optionally substituted with 1 to 3 fluoro; (f) (C1-C6 alkoxy)C(=O)-, (g) (C3-C6 cycloalkyl)C(=O)-, wherein said cycloalkyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 alkoxy, OH, and (C1-C6 alkoxy)C1-C6 alkyl-, or said cycloalkyl is substituted with a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N and O; (h) Ar １ C1-C6 alkyl-, (i) Ar １ (C1-C6 alkyl)C(=O)-, wherein the alkyl moiety is OH, hydroxyC1-C6 alkyl-, C1-C6 alkoxy, R ｍ R ｎ N- or R ｍ R ｎ N-CH ２ -(In the formula, each R ｍ and R ｎ are independently H or C1-C6 alkyl, １ (C1-C6 alkyl)C(=O)-, (j) hetAr ２ C1-C6 alkyl-, wherein said alkyl moiety is optionally substituted with 1 to 3 fluoro, hetAr ２ C1-C6 alkyl-, (k) hetAr ２ (C1-C6 alkyl)C(=O)-, wherein the alkyl portion is optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy; ２ (C1-C6 alkyl)C(=O)-, (l)hetrr ２ C (=O)-、 (m)hetCyc １ C(=O)-、 (n) hetCyc １ C1-C6 alkyl-, (o) R ３ R ４ NC ( = O) - (p)Ar １ N (R ３ )C(=O)-、 (q)hetAr ２ N(R ３ )C(=O)-、 (r) (C1-C6 alkyl)SO ２ (C1-C6 alkyl)SO -, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. ２ -, (s)Ar １ SO ２ -、 (t)hetAr ２ SO ２ -、 (u) N-(C1-C6 alkyl)pyridinonyl, (v)Ar １ C(=O)-、 (w)Ar １ O-C(=O)-、 (x) (C3-C6 cycloalkyl)(C1-C6 alkyl)C(=O)-, (y) (C3-C6 cycloalkyl)(C1-C6 alkyl)SO ２ (C3-C6 cycloalkyl)(C1-C6 alkyl)SO, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. ２ -, (z) Ar １ (C1-C6 alkyl)SO ２ -, (aa)hetCyc １ -O-C(=O)-、 (bb)hetCyc １ CH ２ C(=O)-、 (cc)hetAr ２ ,or (dd) C3-C6 cycloalkyl; Ar １ is phenyl, wherein said phenyl is selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), R ｅ R ｆ N- (wherein, R ｅ and R ｆ are independently H or C1-C6 alkyl), (R ｐ R ｑ N) C1-C6 alkoxy- (wherein R ｐ and R ｑ are independently H or C1-C6 alkyl), and (hetAr ａ ) C1-C6 alkyl- (wherein hetAr ａ is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms; or Ar １ is a phenyl ring fused to a 5- to 6-membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O; hetAr ２ is a 5- to 6-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O, and S, or a 9- to 10-membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms; ２ is selected from halogen, CN, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1 to 3 fluoro), R ｅ R ｆ N- (wherein, R ｅ and R ｆ are independently H or C1-C6 alkyl), OH, (C1-C6 alkoxy)C1-C6 alkoxy-, and C3-C6 cycloalkyl; hetCyc １ is a 4-6 membered saturated heterocyclic ring having 1-2 ring heteroatoms independently selected from N, O, and S, said heterocyclic ring being optionally substituted with one or more substituents independently selected from C1-C6 alkoxy and halogen; R ３ is H or C1-C6 alkyl; R ４ is C1-C6 alkyl, The method comprises reacting a compound of formula 14: 【Chemistry 2】 (In the formula, B, １ , X ２ , X ３ , and X ４ is as defined above, and L ２ is a leaving group or fluorine) The compound of formula 15: 【Transformation 3】 wherein D is as defined above and P １ is an amino protecting group) and subsequently reacting the compound with the protecting group P １ A method of manufacturing comprising removing 2. The method of claim 1, wherein ring D of formula I and formula 15 is a saturated 7-8 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, said ring being optionally substituted with 1 to 4 groups independently selected from (a) halogen, OH, C1-C3 alkyl optionally substituted with 1 to 3 fluoro, or C1-C3 alkoxy optionally substituted with 1 to 3 fluoro, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group.

3. Ring D of formula I and formula 15 is 【Chemistry 4】 where the wavy line represents X １ , X ２ , X ３ , and X ４ and an asterisk indicates the point of attachment to E.

4. The manufacturing method described in claim 3, wherein ring D of formula I and formula 15 is: 【Transformation 5】 5. The method of any one of claims 1 to 4, wherein B in formula I and formula 14 is hydroxy C2-C6 alkyl-, wherein the alkyl moiety is optionally substituted with a C3-C6 cycloalkylidene ring.

6. B in formula I and formula 14 is (hetCyc ａ 5. The method according to claim 1, wherein the alkyl group is C1-C3 alkyl-.

7. X １ is N and X ２ , X ３ , and X ４ The method according to any one of claims 1 to 6, wherein is CH.

8. The compounds of formula I and pharmaceutically acceptable salts and solvates thereof have the formula: 【Transformation 6】 or a pharmaceutically acceptable salt thereof.

9. The compounds of formula I and pharmaceutically acceptable salts and solvates thereof have the formula: 【Transformation 7】 The method according to claim 8, wherein the compound is represented by the formula:

10. The compounds of formula I and pharmaceutically acceptable salts and solvates thereof have the formula: 【Transformation 8】 or a pharmaceutically acceptable salt thereof.

11. The compounds of formula I and pharmaceutically acceptable salts and solvates thereof have the formula: 【Chemistry 9】 or a pharmaceutically acceptable salt thereof.

12. L ２ The method according to any one of claims 1 to 11, wherein is F.

13. P １ The method according to any one of claims 1 to 12, wherein is tert-butoxycarbonyl.

14. Protecting group P １ The method according to any one of claims 1 to 13, wherein the removal is carried out using hydrochloric acid.

15. The protecting group P １ and then functionalizing the nitrogen atom of ring D.

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