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

Abstract

To provide compounds useful in 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 the formula I, and pharmaceutically acceptable salts and solvates thereof. In the formula, A, B, X1, X2, X3, X4, Ring D and E represent specific groups.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 on September 6, 2017, and No. 62 / 554,817 filed on April 27, 2017. No. 62 / 491,164, filed on January 18, 2017; No. 2 / 447,850, filed on October 10, 2016; No. 62 / 406,252, filed on October 10, 2016 No. 6,399,413, 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 of making the compounds, and the compounds in therapy More specifically, the present invention relates to the use of RET-associated diseases and disorders, including RET-associated diseases and disorders. Substituted pyrazolo[1]nes useful for the treatment and prevention of diseases that can be treated with kinase inhibitors. ,5-a]pyridine compounds.

[0003] RET is required for 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, The extracellular portion of RET kinase contains four kinase domains that are 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 kinase domains, one near the cysteine-rich region, and the other near the cytoplasmic region. Contains the ze subdomain.

[0004] RET signaling is a signaling pathway that mediates the expression of glial cell line-derived neurotrophic factor (GDNF) family ligands. This is mediated by the binding of a group of soluble proteins called GFLs, including Neurturin. Also included are cysteine ​​(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 (GFRα) family members. Members of the MYR then bind to RET and connect it to the lipid roughness where RET signaling occurs. The binary complexes recruit β-amyloides to cholesterol-rich membrane subdomains known as β-amyloides. 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 report that the CBL family of ubiquitin ligases function in downregulating RET function. Drop.

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

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

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

[0009] or a pharma- ceutically acceptable salt or solvate thereof, provided herein, , X 1 , X 2 , X 3 , X 4 and Ring D are as defined herein.

[0010] A compound of formula I or a pharma- ceutically acceptable salt thereof, in admixture with a pharma- ceutically acceptable diluent or carrier. Pharmaceutical compositions, including acceptable salts or solvates, are also provided herein.

[0011] A method of inhibiting cell proliferation in vitro or in vivo, comprising administering to the cell an effective amount of a compound of formula I or a pharma- ceutically acceptable salt or solvate thereof, or Also provided herein are methods comprising contacting the 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 pharma- ceutical 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 pharmacopoeial derivative thereof. administering an acceptable salt or solvate, or a pharmaceutical composition as defined herein. Also provided herein is a method, comprising:

[0014] Irritable Bowel Syndrome (IBS) and / or IB in patients in need of 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 pharma- ceutically 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 pharma- ceutically acceptable salt or solvate, or a pharmaceutical composition as defined herein. A method is also provided, which includes:

[0016] Compound of formula I or a pharma- ceutically acceptable salt or solvent thereof for use in therapy. Solvates, or pharmaceutical compositions as defined herein, are also provided 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 pharma- ceutically 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 said patient a an effective amount of a compound of formula I or a pharma- ceutically acceptable salt or solvate thereof, 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 The compound of formula I, or a pharma- ceutically acceptable salt thereof, for use in providing therapy to a cancer patient is also provided. Also provided is a compound or solvate thereof, or a pharmaceutical composition as defined herein.

[0020] A compound of formula I or a pharma- ceutical acceptable salt thereof for use in inhibiting RET kinase activity. Such salts or solvates are also provided herein.

[0021] A compound of formula I or a pharmaceutical composition thereof for use in the treatment of a RET-related disease or disorder. A suitably acceptable salt or solvate thereof, or a pharmaceutical composition as defined herein, is also included herein. Provided in the fine print.

[0022] In the manufacture of a medicament for the treatment of cancer and / or the inhibition of metastasis associated with certain cancers, 2. A compound of formula I or a pharma- ceutically acceptable salt or solvate thereof, 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 pharma- ceutically acceptable salt or solvate thereof, Use of the pharmaceutical compositions as defined herein is 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 pharma- ceutically acceptable salt or solvate thereof are also provided herein. .

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

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

[0027] A method for treating cancer in a patient in need of such treatment, comprising: (a) determining whether the cancer is a cancer that is associated with a RET gene mutation; The present invention relates to a method for the detection of the expression or activity or level of a gene, a RET kinase, or any of the above. (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 of them If the patient is determined to have a cancer associated with dysregulation of the RET gene (e.g., a RET-associated cancer), the patient may be given treatment to treat the cancer. an amount of a compound of formula I, or a pharma- ceutically acceptable salt or solvate thereof, Also provided herein are methods comprising administering the composition.

[0028] Cancer (e.g., RET inhibitor resistant 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, such as a ET-associated cancer), (b) a therapeutically acceptable salt or solvate thereof; and (c) optionally at least one Also provided herein are pharmaceutical combinations comprising one or more pharma- ceutically acceptable carriers. or a pharma- ceutically acceptable salt or solvate thereof, and an additional therapeutic agent The compounds may be administered in separate compositions for simultaneous, separate or sequential use for the treatment of cancer. and a compound of formula I or a pharma- ceutically 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 comprising 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 of treatment.

[0029] A method for reversing or preventing acquired resistance to an anticancer drug comprising administering to a patient a therapeutically effective amount of a compound of formula The compound of formula I or a pharma- ceutically acceptable salt or solvate thereof is used to treat acquired resistance to an anticancer drug. Also provided are methods of administering the composition to a patient at risk of developing or having sexual activity. In some embodiments, a dose of an anti-cancer agent (e.g., a dose of a compound of Formula I) is administered. The method is substantially the same as administering to a patient a compound or a pharma- ceutically acceptable salt or solvate thereof. Administered to the patient at the same time.

[0030] an effective amount of a compound of formula I or 2. Anti-cancer therapy in an individual, comprising administering to the individual a pharma- ceutically acceptable salt or solvate thereof. Also provided herein are methods for delaying and / or preventing the development of cancer that is resistant to a drug. Provided.

[0031] 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 anticancer agent; (a) an effective amount of a compound of formula I; Also provided herein are methods that include administering the product.

[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) The method of treating an individual having a RET-associated cancer comprising administering to said individual a second anti-cancer agent (e.g., a compound of formula I or a RET kinase inhibitor thereof Methods that include administering a pharma- ceutically acceptable salt or solvate are also provided.

[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 T kinase inhibitor), a compound of formula I or a pharmaceutical Also provided is a method comprising administering an acceptable salt or solvate of

[0034] A method for treating irritable bowel syndrome (IBS) in a patient in need of such treatment. (a) IBS is characterized in that the RET gene, the RET kinase, or the expression or non-expression of either of them (b) determining whether the IBS However, the RET gene, the RET kinase, or the expression or activity of either of them is not specifically inhibited. If it is determined that the patient is associated with dysregulation of levels of IL-1, the patient is administered a therapeutically effective amount of a compound of formula I. or a pharma- ceutically 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 pharma- ceutically acceptable salt or solvate thereof (b) an additional therapeutic agent; and (c) optionally at least one pharma- ceutically acceptable carrier. Also provided herein are pharmaceutical combinations comprising administering a compound of formula I or the amount of the pharma- ceutically 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 combined preparations 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 pharma- ceutically acceptable salt or solvate thereof Also provided herein are methods for determining whether a particular

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

[0038] Unless otherwise defined, all technical and scientific terms used herein are intended to be understood as meaning the invention. The term has the same meaning as commonly understood by a person skilled in the art to which it pertains. 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 the event of conflict, the present specification, including definitions, will prevail. Priority shall be given to the following:

[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 PREFERRED EMBODIMENTS

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

[0041] and pharma- ceutically acceptable salts and solvates thereof, wherein

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

[0043] A is H, CN, Cl, CH 3 -, CH 3 CH 2 -, cyclopropyl, -CH 2 C.N., or -CH(CN)CH 3 and

[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 portion 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 portion is a 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 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-, hetAr1 But N, O, and S 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-, Each of the 4 alkyl moieties and the C1-C6 alkyl moieties is optionally and independently selected from 1 to 3 fluoro-substituted (C1-C4 alkyl)C(=O)O-C1-C6 alkyl Ru-, or

[0057] (m)(R 1 R 2 N) C(=O)C1-C6 alkyl-, where R 1 and R 2 Independence 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 A 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 or optionally substituted with one or more substituents independently selected from 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 which 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 the rings is (a) a C1- optionally substituted with halogen, OH, or 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) is optionally substituted with an oxo group;

[0060] E,

[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 kill-,

[0064] (d) (C1-C6 alkyl)C(=O)-, the alkyl portion being 1 to 3 Fluoro or R g R h N-substituent (wherein R G and R H are independent, H or (C1-C6 alkyl)C(=O )-,

[0065] (e) (hydroxy C2-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 cycloalkyl has 1 to 3 ring heteroatoms independently selected from N and O substituted with a 5-6 membered heteroaryl ring having the formula: (C3-C6 cycloalkyl)C (=O)-,

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

[0069] (i) Ar 1 (C1-C6 alkyl)C(=O)-, the alkyl moiety being OH , hydroxyC1-C6 alkyl-, C1-C6 alkoxy, R m R nN- or R m R n N-CH 2 -(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)-,

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

[0071] (k)hetAr 2 (C1-C6 alkyl)C(=O)-, where the alkyl portion , optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy It is being done, 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)SO 2 -, wherein the alkyl portion is 1 to 3 fluoro Optionally substituted with (C1-C6 alkyl)SO 2 -,

[0079] (s)Ar 1 SO 2 -,

[0080] (t)hetAr 2 SO 2 -,

[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)SO 2 -And Alki the alkyl moiety is optionally substituted with 1 to 3 fluoro; (C1-C6 alkyl)SO 2 -,

[0086] (z)Ar 1 (C1-C6 alkyl)SO 2 -,

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

[0088] (bb)hetCyc 1 CH 2 C(=O)-,

[0089] (cc)hetAr 2 ,or

[0090] (dd) C3-C6 cycloalkyl,

[0091] 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, C1-C6 alkyl), (R p R q N ) C1-C6 alkoxy- (wherein R p and R q are independently H or C1-C6 ar Kill), and (hetAr a ) C1-C6 alkyl-(wherein, hetAr a but, A 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms, or Ar 1 but, A 5- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O. is a phenyl ring fused to

[0092] hetAr 2 are independently selected from N, O, and S; 5-6 membered heteroaryl ring having 1 to 3 ring nitrogen atoms, or 0-membered bicyclic heteroaryl ring, hetAr 2 But halogen, CN, C1-C6 Al 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, 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 4-6 membered saturated heterocyclic ring having the formula is 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 pharma- ceutically 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" includes -F (as used herein as "fluoro" or or "fluoros"), -Cl, -Br, and Implies -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 linear or branched monovalent hydrocarbon radical of 2 to 6, or 3 to 6 carbon atoms Examples include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, and isobutyric acid. 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 attached to an oxygen atom. A saturated linear or branched monovalent alkoxy radical of 1 to 6 carbon atoms. Examples are The aryl groups are 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-" refers to a group in which one of the carbon atoms is an alkyl group. each of which is substituted with 1 to 6 C1-C6 alkoxy groups as defined in the specification A saturated linear or branched monovalent radical of 1 to 6 carbon atoms or 2 to 6 carbon atoms. Examples are As for methoxymethyl (CH 3 OCH 2 -) and methoxyethyl (CH 3 OCH 2 C H 2 -) are mentioned.

[0101] As used herein, "hydroxy C1-C6 alkyl-" and "hydroxy C2-C The term "6 alkyl-" refers to a group in which one of the carbon atoms is replaced with a hydroxy group. Saturated linear or branched 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 consisting of carbon atoms. A saturated straight or branched chain of 3 to 6 carbon atoms, two of which are substituted with hydroxy groups. Refers to a branched 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 R 1 and R 2 is as defined herein, These radicals refer to C1-C6 alkyl or C2-C6 radicals, 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 hetAr 1 is defined herein "C1-C6 alkyl radical" refers to a C1-C6 alkyl radical as defined herein.

[0105] As used herein, the term "C3-C6 cycloalkyl" includes cyclopropyl, It 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- refers to 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 aryl radical, respectively, as defined in Pointing 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 aryl groups 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 HetCyc a In this specification, refers to a C1-C3 alkyl radical as defined herein, 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. It 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 any of the carbon atoms One of them is hetAr 2 Substituted with hetAr 2is defined herein as "C1-C6 alkyl radical" 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 HetCyc 1 is defined herein "C1-C6 alkyl" refers to a C1-C6 alkyl radical 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 other than the carbon bearing an oxo group. The pyridin-2(1H)-one ring may be any of the ring carbon atoms of Examples include the following structures: [ka]

[0113] As used herein, the term "heterospirocyclic ring" refers to a spiro ring bonded via a carbon atom. are linked by cyclic bonds, each ring having 4 to 6 ring atoms (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) having the structure It can be represented. [ka]

[0115] As used herein, the term "compound" refers to all stereoisomers, geometrical isomers, and / or isomers of a depicted structure. All isomers, tautomers, and isotopes are intended to be included. Compounds herein identified by name or structure in the form , and other tautomeric forms are intended to be included.

[0116] As used herein, the term "tautomer" refers to compounds that have a distinct arrangement of atoms, refers to compounds that exist in easy and rapid equilibrium, and the compounds provided herein are When a compound has tautomeric forms, all tautomeric forms are It is contemplated that tautomeric forms are within the scope of the present invention and the naming of the compounds includes any tautomeric forms. Exemplary tautomerizations include keto to enol, Amides to imides, lactams to lactims, enamines to imines, and enamines to imines. These include, but are not limited to, tautomerization from pheno to (different) enamines. 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 may 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 is independent, CH , CF, or CCH 3 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 is independent, CH , CF, or CCH 3 or N and X 1 , X 2 , X 3 , and X 4 One of is N, and the remainder are independently CH, CF, or CCH 3 Certain embodiments of formula I are 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 B 4 is CH.

[0120] In certain embodiments of formula I, X 1 , X 2 , X 3 , and X 4 is independent, CH , CF, or CCH 3 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 And X 4 are independently CH, CF, or CCH 3 In one embodiment, X 1 oh And X 3 is N and X 2 and X 4 is CH. In certain embodiments of formula I, Hey, 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 , C.H.

[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 CH 3 -It is.

[0125] In certain embodiments of formula I, A is CH 3 CH 2 -It is.

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

[0127] In certain embodiments of formula I, A is -CH 2 It is CN.

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

[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. Pyrene, 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 selected from 1 to 3 fluoro or C3-C6 cycloalkylidene rings. In certain embodiments of formula I, wherein B is hydroxyC2-C6 alkyl-, the alkyl portion being 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 dihydrooxyC3-C6 alkyl-. Non-limiting examples include 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 is independent, 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 (R1 R 2 N) C1-C6 alkyl-. Certain embodiments of formula I In this embodiment, B is (R 1 R 2 N) C1-C6 alkyl-, where the alkyl portion is , optionally substituted with OH, 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 aryl groups are each independently selected from the group consisting of 5-6 membered heteroaryl rings having the formula: optionally substituted with alkyl substituents, 1 It is C1-C3 alkyl-. In certain embodiments, 1 is 1 to 3 independently selected from N and O A 5-6 membered heteroaryl ring having a ring heteroatom of C1-C6 alkyl, optionally 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 A 4-6 membered heterocyclic ring having 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 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O a ring, which is selected from the group consisting of OH, C1-C6 alkyl (optionally substituted with 1-3 fluoro), hydroxyl, oxyC1-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). Illustrative examples include the following structures: [ka]

[0139] In certain embodiments of formula I, B is C3-C6 cycloalkyl-, 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-C6Al Kill - R 1 and R 2 are independently H or C1-C6 alkyl (1 to 3 (R 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 dicyclic ring having two nitrogen ring 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; 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; or (c) is 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) having two ring nitrogen atoms and, optionally, a third ring heteroatom which is oxygen. (iii) a saturated 7- to 8-membered bridged heterocyclic ring having two ring nitrogen atoms; a heterospirocyclic ring, or (iv) a saturated 9- to 10-membered bicyclic fused ring having two ring nitrogen atoms and each of the rings 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 substituted ring 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 The phrase "having two ring nitrogen atoms" in the case of a heterocyclic ring means that the ring nitrogen atoms are means two nitrogen atoms as shown in ring D of formula I, wherein ring D is represented by the following structure: It may be possible, [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 represents the point of attachment to the E group, and the ring B is (a) any of halogen, OH, and 1 to 3 fluoro. C1-C3 alkyl 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, which is substituted with oxo. In one embodiment, Ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. ring, which is substituted with a C3-C6 cycloalkylidene ring. In the formula (I), 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 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 ~3 fluoro or 1-3 fluoro 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 Ring D indicates the point of attachment to the ring containing halo. 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. In one embodiment, ring D is unsubstituted. In one embodiment, ring D is substituted with oxo. In one embodiment, Ring D is a C3-C6 cyclopropyl In one embodiment, Ring D is substituted with an oxo ring. 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 being In one embodiment, the alkyl group is substituted with 1 to 4 C1-C3 alkyl groups, each of which is optionally substituted with one or more C1-C3 alkyl groups. wherein ring D is unsubstituted or has 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. Ring D is (a) a C1-C3 ring 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 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 is one or two C1-C3 alkyl groups, e.g., 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. Ring D is (a) a C1-C3 ring 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 E is (a) hydrogen, or (c) one to three fluoro groups. (C1-C6 alkoxy)C1-C6 alkyl- substituted with 1 to 3 fluoro (C1-C6 alkyl)C(=O)- optionally substituted with b, (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-, optionally substituted or having 1 to 3 ring heteroatoms independently selected from N and O; Optionally substituted with a 5-6 membered heteroaryl ring having a (C3-C6 cycloalkyl )C(=O)-, (h)Ar 1 C1-C6 alkyl-, (i) Ar 1 (C1-C6 Alky C(=O)-, the alkyl moiety being OH, hydroxyC1-C6 alkyl - or C1-C6 alkoxy optionally substituted, 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)-, where the alkyl portion , 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 Alky 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. Ring D is (a) a C1-C3 ring 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) 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. Ring D is (a) a C1-C3 ring 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) E is optionally substituted with 1 to 3 fluoro (C1 In one embodiment, ring D is selected from the group consisting of two 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. Ring D is (a) a C1-C3 ring 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) E is optionally substituted with 1 to 3 fluoro (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. Ring D is (a) a C1-C3 ring 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) E is optionally substituted with 1 to 3 fluoro (hydro). In one embodiment, ring D is a C(oxyC2-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. Ring D is (a) a C1-C3 ring 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) Optionally substituted with an oxo group, 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. Ring D is (a) a C1-C3 ring 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) Optionally substituted with oxo groups, E is (C3-C6 cycloalkyl)C(=O)-. wherein the cycloalkyl is (C1-C6 alkoxy)C1-C6 alkyl-, is a 5-6 membered heteroaromatic ring having 1-3 ring heteroatoms independently selected from N and O; Optionally substituted with an aryl ring, e.g., pyridinyl, (C3-C6 cycloalkyl)C In one embodiment, Ring D is a saturated 6-membered ring having two 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. Ring D is (a) a C1-C3 ring 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) E is optionally substituted with an oxo group; 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. Ring D is (a) a C1-C3 ring 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) E is optionally substituted with an oxo group; 1 (C1-C6 alkyl)C(=O)- The alkyl moiety is OH, hydroxyC1-C6 alkyl, C1-C6 alkoxy, Kishi, R m R n N- or R m R n N-CH 2 -, and each R m Oh BiR n are independently H or C1-C6 alkyl; Ar 1 is defined for formula I As stated above, Ar 1 (C1-C6 alkyl)C(=O)-. In one embodiment, ring D is a saturated 6-membered heterocyclic ring having two ring nitrogen atoms. In one embodiment, Ar 1 is not replaced 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. Ring D is (a) a C1-C3 ring 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) is optionally substituted with an oxo group, and E is hetAr 2 C1-C6 alkyl- the alkyl moiety is optionally substituted with 1 to 3 fluoro; 2 is the formula 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, Ring D is cyclopro In one embodiment, hetAr is substituted with a pyridine ring. 2 has 1-2 ring nitrogens In one embodiment, hetAr is a 5-6 membered heterocyclic ring having a nitrogen atom. 2 Ha, Hello aryl, 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. Ring D is (a) a C1-C3 ring 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) is optionally substituted with an oxo group, and E is 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 It is, 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 Alky The alkyl portion of hetA(=O)- is unsubstituted. r 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). 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 1 to 2 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. Ring D is (a) a C1-C3 ring 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) is optionally substituted with an oxo group, and E is hetAr 2 C(=O)-, hetA r 2 is as defined for formula I; 2 C(=O)-. In an embodiment, 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 alkyl group 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 2is a 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 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, 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. Ring D is (a) a C1-C3 ring 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) is optionally substituted with an oxo group, and E is hetAr 1 C(=O)-, hetCy c 1 is as defined for formula I. In one embodiment, ring D is selected from two rings In one embodiment, ring D is a substituted 6-membered heterocyclic ring having a nitrogen atom. In one embodiment, hetCyc 1 is a 4-6 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. Ring D is (a) a C1-C3 ring 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) E is optionally substituted with an oxo group; 1 C1-C6 alkyl-, hetCyc 1 is 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 In one embodiment, hetCyc is unsubstituted. 1 has 4 to 6 ring oxygen atoms 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. Ring D is (a) a C1-C3 ring 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) E is optionally substituted with an oxo group; 3 R 4 NC(=O)-, R 3 and R 4 is as defined for formula I. In one embodiment, ring D is a ring In one embodiment, ring D is a substituted 6-membered heterocyclic ring having a nitrogen atom. 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. Ring D is (a) a C1-C3 ring 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) is optionally substituted with an oxo group, and E is hetAr 2 and hetAr 2 is expressed in formula I In one embodiment, ring D has two ring nitrogen atoms. and Ring D is unsubstituted. Ar 2 is a 5-6 membered heterocyclic ring having 1-2 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 aryl 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 1-2 ring nitrogen atoms, and and optionally substituted with koxy. Non-limiting examples include the structures: [ka]

[0167] In one embodiment of Formula I, Ring D has two ring nitrogen atoms and, optionally, oxygen. and a saturated 7- to 8-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. As used herein, when Ring D is a saturated 7-8 membered bridged heterocycle, the term "two rings" refers to a ring having a ring structure of 7 to 8 members. 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. A nitrogen atom is a ring nitrogen atom, and one of the ring nitrogen atoms is X 1 , X 2 , X 3 , and X 4 Connected to 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 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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-phenylene having 2 to 3 ring heteroatoms independently selected from N and O. In one embodiment, when a 9-membered bridged heterocyclic ring, the rings 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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 structure is a saturated seven-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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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 represented by the formula: OH, C1-C3 alkyl optionally substituted with 1 to 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) 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. The ring D is a saturated 7- to 9-membered bridged heterocyclic ring having a ring heteroatom of the formula (a) C1-C3 alkyl optionally substituted with 1-3 fluorine, OH, 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, or (c) (C1-C6 alkoxy). ) C1-C6 alkyl-, (d) (C1-C6 alkyl) C(=O)-, (e) (hydro (C2-C6) alkyl) C(=O)-, (f) (C1-C6 alkoxy) C(=O) -, (g) (C3-C6 cycloalkyl)C(=O)-, (h) Ar 1 C1-C6 Alky Ru-, (i) Ar 1 (C1-C6 alkyl)C(=O)-, where the alkyl portion , 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)SO 2 -, (t)hetAr 2 SO2 -, (u) N-(C1-C6 alkyl)pyridinonyl, (v) Ar 1 C(=O)- , (w)Ar 1 OC(=O)-, (x)(C3-C6 cycloalkyl)CH 2 C(=O) -, (y) (C3-C6 cycloalkyl) (C1-C6 alkyl) SO 2 -, (z)Ar 1 (C1-C6 alkyl)SO 2 -, (aa)hetCyc 1 -OC(=O)-, (BB )hetCyc 1 -CH 2 -C(=O)-, and (cc)hetAr 2 , 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 structure is a saturated 7-8 membered bridged heterocyclic ring; [ka]

[0178] In the formula, the wavy line represents X 1 , X2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The X of 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) Ar 1 C1-C6 alkyl -, (i) Ar 1 (C1-C6 alkyl)C(=O)-, the alkyl portion being Optionally substituted with OH, hydroxyC1-C6 alkyl, or C1-C6 alkoxy 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)SO 2 -, (t)hetAr 2 SO 2 -, (u) N-(C1-C6 alkyl)pyridinonyl, (v) Ar 1 C(=O) -, (w)Ar 1 OC(=O)-, (x)(C3-C6 cycloalkyl)CH 2 C(=O )-, (y) (C3-C6 cycloalkyl) (C1-C6 alkyl) SO 2 -, (z)A r 1 (C1-C6 alkyl)SO 2 -, (aa)hetCyc 1 -OC(=O)-, (b b) hetCyc 1 -CH 2 -C(=O)-, and (cc)hetAr 2 The group consisting of wherein Ar 1 ,hetAr 2 , R 3 , and hetCyc 1 According to 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. and a saturated 7- to 8-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. and 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 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: This 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being represented by (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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group, E is (C1-C6 alkyl)C(=O)-, Minutes, 1 to 3 fluoro or R g R h N-substituent (wherein R g and R h is independent (C1-C6 alkyl, 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is optionally substituted with 1-3 fluoro (hydroxy C2-C6 alkenyl). 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is C3-C6 cycloalkyl)C(=O)-, The groups are 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)-, where 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 7-8 membered bridged heterocyclic ring having a nitrogen atom. It 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 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 described above, Ar 1 In one embodiment, E is Ar 1 C1-C6 alkyl-, Ar 1 is halogen, C1-C6 alkyl (1- 3 fluoro optionally substituted), C1-C6 alkoxy (optionally substituted with 1 to 3 fluoro (R p R q N) C1-C6 alkoxy- (wherein R p and R q is H or C1-C6 alkyl), and (hetAr a )C1-C6A Aryl-(wherein, a is a 5-6 membered heteroaryl having 1-2 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 7-8 membered bridged heterocyclic ring having 1 to 8 ring nitrogen atoms. is represented by the following structure: [ka]

[0194] 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 trisrisk 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)-, where the alkyl portion , OH, hydroxy C1-C6 alkyl, C1-C6 alkoxy, R m R n N-, or R m R n N-CH 2 -, wherein each R m and R n is independent, H or C1-C6 alkyl, 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 substituted with one or more halogens. and 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]

[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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is hetAr 2 C1-C6 alkyl-, the alkyl moiety being Optionally substituted with 1 to 3 fluoro, hetAr 2 is as defined for formula I HetAr 2 In one embodiment, hetAr 2 is a 5-6 membered ring heteroatom having 1-3 ring heteroatoms independently selected from N, O, and S. Heteroaryl ring or 9-10 membered bicyclic heteroaryl having 1-3 ring nitrogen atoms Ar2 is halogen, CN, C1-C6 alkyl (1 to 3 fluorines) 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 7-8 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 trisrisk 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, hydroxyC1-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 6-membered ring having 1 to 2 nitrogen atoms. and is a 6-membered heteroaryl ring, optionally substituted with one or more halogens. In one embodiment, Ring D is unsubstituted. In one embodiment, Ring D is substituted with two ring nitrogens. In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having the following ring structure: 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is Ar 1 C1-C6 alkyl-, hetAr 2 Regarding formula I As defined by Ar 1 In one embodiment, hetAr 2 is a 6-membered heteroaryl ring having 1-2 ring nitrogen atoms and halo aryl, C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and (C1- C6 alkoxy) C1-C6 alkoxy-, 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 trisrisk 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. and a saturated 7- to 8-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is hetCyc 1 C(=O)-, hetCyc 1 According to formula I As defined in 1 In one embodiment, 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 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 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 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 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 As defined for Ar 1 N(R 3 )C(=O)-. In one embodiment Hey, Ar 1 is unsubstituted or C1-C6 alkoxy (1 to 3 fulvic acids) 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 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. 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, place unsubstituted or C1-C6 alkoxy (optionally substituted with 1-3 fluoro In one embodiment, Ring D is a saturated 7-membered ring having two 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. and E is (C1-C6 alkyl)SO 2 - and the alkyl portion is 1 to 3 (C1-C6 alkyl)SO optionally substituted with one fluoro 2 - One implementation 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is hetAr 2 SO 2 - and hetAr 2 is defined for formula I In one embodiment, hetAr 2 is not replaced 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 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 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 7-8 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is Ar 1 C(=O)-, and Ar 1 is defined as for formula I In one embodiment, Ar 1is halogen, C1-C6 alkyl (1 to 3 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 or Ar 1 is a 5-6 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is Ar 1OC(=O)-, 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 tririsk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. and E is C3-C6 cycloalkyl)CH 2 C(=O)-, alkyl The moiety is optionally substituted with 1 to 3 fluoro, 2In one embodiment, ring D is a saturated 7-membered ring having two 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. and E is (C3-C6 cycloalkyl)(C1-C3 alkyl)SO 2 -Yes The alkyl portion is optionally substituted with 1 to 3 fluoro groups, (C3-C6 cycloalkyl). (C1-C3 alkyl)SO 2 In one embodiment, ring D is 2 In one embodiment, ring D is a saturated 7-8 membered bridged heterocyclic ring having 1 to 8 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is Ar 1 (C1-C6 alkyl)SO 2 - and Ar 1 According to formula I In one embodiment, Ar 1 is not replaced. 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 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 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 trisrisk 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. and a saturated 7- to 9-membered bridged heterocyclic ring having a third ring heteroatom, the ring being 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 4 groups, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group. E is hetCyc 1 -CH 2 -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 trisrisk 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 1-2 ring nitrogen atoms and C1-C6 alkoxy In one embodiment, Ring D is a saturated alkyl group having two ring nitrogen atoms. In one embodiment, ring D is represented by the following structure: R, [ka]

[0232] 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 trisrisk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; 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 But, X 1 , X 2 , X 3 , and X 4 and the other ring nitrogen atom is bonded to a ring containing the 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 structures: [ka] [ka]

[0234] 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 a halogen atom, OH, 1 to 3 alkyl groups, each of which is selected from the group consisting of aryl, aryl, aryl and aryl; 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 substituted alkoxy; 6 cycloalkylidene ring, or (c) an oxo group. In the above, ring D is unsubstituted.

[0235] When ring D is a saturated 7- to 11-membered heterospirocyclic ring having two ring nitrogen atoms, In an embodiment, 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 ring 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 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, (a) halogen, OH, 1-3 fluoro, optionally 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; 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 portion 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 SO 2 -, (t)hetAr 2 SO 2 -, (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, ring D is unsubstituted.

[0241] In one embodiment, Ring D has two ring nitrogen atoms represented by the 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 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 4 NC(=O)-, In one embodiment, Ring D is unsubstituted.

[0243] In one embodiment, ring D is a saturated 7-membered ring having two nitrogen atoms. 1 to 11-membered heterospirocyclic ring, the ring being selected from the group consisting of (a) halogen, OH, 1 to 3 full rings, C1-C3 alkyl optionally substituted with or optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) optionally substituted with an oxo group, and E is hydrogen. In one embodiment, the ring D is represented by the 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 trisrisk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; or (c) optionally substituted with oxo groups, and E is (b) optionally substituted with 1 to 3 fluoro groups. In one embodiment, the ring D is a C1-C3 alkyl substituted with 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 trisrisk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; or (c) optionally substituted with an oxo group, E being (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, ring D is (C1-C6 alkyl)C(=O)-. It is represented by the following structure: [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 trisrisk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; or (c) optionally substituted with an oxo group, E being (C1-C6 alkoxy)C(= In one embodiment, the ring D is represented by the 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 trisrisk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; or (c) optionally substituted with an oxo group, and E is hetAr 2C(=O)- ,hetAr 2 is as defined for formula I. In one embodiment, het Ar 2 is a 5-6 membered heterocyclic ring having 1-2 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 aryl 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 1-2 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 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 tririsk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; 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 trisrisk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; or (c) optionally substituted with an oxo group, and E is Ar 1 SO 2 - 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 1 independently selected from the group consisting of methoxy (optionally substituted with 1 to 3 fluoro); In one embodiment, Ring D is a phenyl optionally substituted with the above substituents. In one embodiment, the ring D is represented by the 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 tririsk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; or (c) optionally substituted with an oxo group, and E is hetAr 2 SO 2 - and h etAr 2 is as defined for formula I. In one embodiment, 2is 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 group. In one embodiment, Ring D is optionally substituted with koxy. In one embodiment, the ring D is represented by the 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 tririsk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; 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 halogen , C1-C6 alkyl (optionally substituted with 1 to 3 fluoro), and C1-C6 a 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 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 tririsk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; 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 In one embodiment, hetA is a 5-6 membered heterocyclic ring having 1 to 2 ring nitrogen atoms. r 2 is 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, he is optionally substituted with one or more substituents selected from the group consisting of aryl, ... tAr 2 is a 6-membered ring having 1-2 ring nitrogen atoms and is C1-C6 alkoxy. It is optionally substituted. In one embodiment, the ring D is unsubstituted. In one 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 tririsk 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 alkoxy optionally substituted with 1 to 3 fluoro. (b) 1 to 4 groups independently selected from koxy; or (c) optionally substituted with an oxo group, and E is a 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 tririsk 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; 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 includes The ring nitrogen atoms are the two ring nitrogen atoms shown in ring D of formula I, and one of the ring nitrogen atoms But, X 1 , X 2 , X 3 , and X 4 and the other ring nitrogen atom is bonded to a ring containing the 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 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 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; or (c) optionally substituted with an oxo group, and E is as defined for formula I. It 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; or (c) optionally substituted with an oxo group, E being hydrogen or (C1-C6 alkoxy). In one embodiment, ring D is represented by the 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 trisrisk 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; 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 X 1 , X 2 , X 3 , and X 4 indicates the point of attachment of ring D to the ring containing The trisrisk 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; or (c) optionally substituted with an oxo group, E being (C1-C6 alkoxy)C( In one embodiment, ring D is represented by the 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 trisrisk 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 comprises a compound of formula IA, wherein:

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

[0276] A is H, CN, Cl, CH 3 -, CH 3 CH 2 -, cyclopropyl, -CH 2 C.N., or -CH(CN)CH 3 and

[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 portion 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 portion is a 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 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 2 are independently H or C1-C6 alkyl (1 to 3 fluoro (R 1 R 2 N) C1-C6 alkyl-,

[0284] (g)hetAr 1C1-C3 alkyl-, hetAr 1 But N, O, and S 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-, Each of the 4 alkyl moieties and the C1-C6 alkyl moieties is optionally and independently selected from 1 to 3 fluoro-substituted (C1-C4 alkyl)C(=O)O-C1-C6 alkyl Ru-, or

[0290] (m)(R 1 R 2 N) C(=O)C1-C6 alkyl-, where R 1 and R 2 Independence and H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro). , (R 1 R2 N) C(=O) C1-C6 alkyl-;

[0291] hetCyc a - has 1 to 2 ring heteroatoms independently selected from N and O A 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 or optionally substituted with one or more substituents independently selected from 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 represents the point of attachment to the E group, and the ring B is (a) any of halogen, OH, and 1 to 3 fluoro. C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from 1-C3 alkoxy; or (c) is optionally substituted with an oxo group.

[0294] E,

[0295] (a) hydrogen,

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

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

[0298] (e) (hydroxy C2-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 the cycloalkyl is a ring heteroatom 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) Ar 1 (C1-C6 alkyl)C(=O)-, the alkyl moiety being OH , hydroxyC1-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-, the alkyl moiety being 1 to 3 fluorines. Arguments are optionally substituted with Ar. 2 C1-C6 alkyl-,

[0304] (k)hetAr 2 (C1-C6 alkyl)C(=O)-, where the alkyl portion , optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy It is being done, 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 (hetAr alkyl), and (hetAr a ) C1-C6 alkyl-(wherein, hetAr a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms) phenyl optionally substituted with one or more substituents selected from the group consisting of aryl, aryl, aryl and aryl; 1 is a 5- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O is a phenyl ring fused to a ring of the formula

[0311] hetAr 2 are independently selected from N, O, and S; 5-6 membered heteroaryl ring having 1 to 3 ring nitrogen atoms, or 0-membered bicyclic heteroaryl ring, hetAr 2 But halogen, CN, C1-C6 Al 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, 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

[0312] hetCyc 1 is 1 to 2 ring heteroatoms independently selected from N, O, and S; and the heterocyclic ring is a 4-6 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 In 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 a 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 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-, where the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. It is preferably a hydroxy C2-C6 alkyl-.

[0323] 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. In one embodiment, the aryl 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. 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 hydroxyC2-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 substituted.

[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 2 C1-C6 alkyl-, or Ar 1 (C1-C6 alkyl)C(= O)-, and Ar 1 is unsubstituted phenyl, hetAr 2 has 1-2 ring nitrogen atoms 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 1-2 ring nitrogen atoms and is a 6-membered heterocyclic ring, and is optionally substituted with halogen, C1-C6 alkyl (1 to 3 fluoro). Optionally substituted), 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:

[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-, where the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. E is hydroxy C2-C6 alkyl-, 1 C1-C6 alkyl, hetAr 2 C1-C6 alkyl, the alkyl portion being optionally 1 to 3 fluoro. is replaced by, hetAr 2 C1-C6 alkyl, or Ar 1 (C1-C6 Alky 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-, the alkyl moiety being 1 to 3 optionally substituted with fluoro, hetAr 2 C1-C6 alkyl-, or Ar 1 (C1-C6 alkyl)C(=O)-, 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-, 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 defined.

[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)-, the alkyl moiety being OH, hydroxyl Ar optionally substituted with C1-C6 alkyl- or C1-C6 alkoxy; 1 (C1-C6 alkyl)C(=O)-, 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 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-, het Ar 2 C1-C6 alkyl-, wherein the alkyl portion is optionally substituted with 1 to 3 fluoro. Converted to hetAr 2C1-C6 alkyl-, or Ar 1 (C1-C6 alkyl )C(=O)-, and Ar 1 and hetAr 2 is defined as 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-, r 1 is as defined for formula IA. In one embodiment, the alkyl group B is 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 hydroxyC2-C6 alkyl -, wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring. , hydroxyC2-C6 alkyl-, and E is hetAr 2 C1-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, hetAr2 In one embodiment, the alkyl of the B group is 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 a C3-C6 cycloalkylidene. hydroxy C2-C6 alkyl-, optionally substituted on the ring, and E is Ar 1 (C 1-C6 alkyl)C(=O)-, where 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 Ar 1 (C1-C6 alkyl)C(=O)-. In one embodiment, Ar 1 In one embodiment, B is hydroxy C2-C6 alkyl. alkyl-, where 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 X 4 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) 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)-, hetCyc a and Ar 1 Regarding formula IA, As defined in

[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-, Ar1 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 a compound of formula IB, wherein:

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

[0342] A is H, CN, Cl, CH 3 -, CH 3 CH 2 -, cyclopropyl, -CH 2 C.N., or -CH(CN)CH 3 and

[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 portion 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 portion is a 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 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-, hetAr 1 But N, O, and S 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-, Each of the 4 alkyl moieties and the C1-C6 alkyl moieties is optionally and independently selected from 1 to 3 fluoro-substituted (C1-C4 alkyl)C(=O)O-C1-C6 alkyl Ru-, or

[0356] (m)(R 1 R 2 N) C(=O)C1-C6 alkyl-, where R 1 and R 2 Independence 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 A 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 or optionally substituted with one or more substituents independently selected from 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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;

[0360] E,

[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)-, the alkyl moiety being 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 Optionally substituted with Ar 1 (C1-C6 alkyl)C(=O)-,

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

[0371] (k)hetAr 2 (C1-C6 alkyl)C(=O)-, where the alkyl portion , optionally substituted with OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy It is being done, 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)SO 2 - wherein the alkyl moiety is 1 to 3 fulvic (C1-C6 alkyl)SO optionally substituted with 2 -,

[0378] (t)hetAr 2 SO 2 -,

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

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

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

[0382] (x) (C3-C6 cycloalkyl)CH 2 C(=O)-,

[0383] (y) (C3-C6 cycloalkyl)(C1-C6 alkyl)SO 2 -,

[0384] (z)Ar 1 (C1-C6 alkyl)SO 2 -,

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

[0386] (bb)hetCyc 1 -CH 2 -C(=O)-, or

[0387] (cc)hetAr 2 , and

[0388] Ar1 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 (hetAr alkyl), and (hetAr a ) C1-C6 alkyl-(wherein, hetAr a is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atoms) phenyl optionally substituted with one or more substituents selected from the group consisting of aryl, aryl, aryl and aryl; 1 is a 5- to 6-membered heterocyclic ring having 1 to 2 ring heteroatoms independently selected from N and O is a phenyl ring fused to a ring of the formula

[0389] hetAr 2 are independently selected from N, O, and S; 5-6 membered heteroaryl ring having 1 to 3 ring nitrogen atoms, or 0-membered bicyclic heteroaryl ring, hetAr 2 But halogen, CN, C1-C6 Al 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, 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

[0390] hetCyc 1 is 1 to 2 ring heteroatoms independently selected from N, O, and S; and the heterocyclic ring is a 4-6 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 In 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro or C1-C3 alkyl optionally substituted with 1 to 3 fluoro (b) 1 to 4 groups independently selected from C1-C3 alkoxy; or (c) is 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 trisrisk indicates the point of attachment to E, and ring D is unsubstituted.

[0400] In one embodiment of formula IB, B is a C1- optionally substituted with 1 to 3 fluoro. C6 alkyl, (C1-C6 alkoxy)C1- optionally substituted with 1 to 3 fluoro C6 alkyl, hydroxyC2-C6 alkyl, and the alkyl portion is C3-C6 hydroxy Hydroxy C2-C6 alkyl, optionally substituted with a chloroalkylidene ring, hetA r 1 C1-C3 alkyl-, or (hetCyc a ) C1-C3 alkyl-, h etAr 1 and hetCyc a is as defined for formula IB.

[0401] In one embodiment of formula IB, B is a 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 hydroxy C2-C6 alkyl- wherein the alkyl portion 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- , hetCyca 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 In 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 a C1-C6 alkyl optionally substituted with 1 to 3 fluoro. 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 In 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-, where 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 X 4 is C-H .

[0409] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In 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 , C.H.

[0410] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 4 is CH. In one embodiment, X 1 and X 3 is N and X2 and X 4 is CH.

[0411] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In 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 In equation IB, In one embodiment, X 1 is N and X 2 , X 3 ,oh And X 4 is CH. In one embodiment, X 1 and X 3 is N and X 2 Oh B 4 is CH.

[0412] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In 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 formula As defined for IB. In one embodiment, X 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.

[0413] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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 is optionally substituted with 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 , 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 In 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-, where 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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 is optionally substituted with an oxo group. In one embodiment, 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.

[0417] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 B 3 is N and X 2 and X 4 is CH.

[0419] In one embodiment of formula IB, X 1 is N and X 2 , X 3, and X 4 In 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 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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 is optionally substituted with 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 X 2 , X 3 , and X 4 In 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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 is optionally substituted with 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, hetAr 2C1-C6 Alkyl-, hetAr 2 C(=O)-, Ar 1 R 3 NC(=O)- or (C1-C 6)SO 2 - and hetAr 2 , Ar 1 , and R 3 For formula IB, As defined herein. In one embodiment, 2 is independent of N and O A 5- to 6-membered heteroaryl ring having 1 to 2 ring heteroatoms selected from the following: 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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)SO 2 - 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 B 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 In one embodiment of formula IB, 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 and X 2 and X 4 teeth , C.H.

[0428] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; 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 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 In CH Yes or X 1 and X 3 is N and X2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is (C1-C6 alkylene; RuKil)SO 2 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 In 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. C6 alkyl-, or hydroxyC2-C6 alkyl-, where 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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)SO 2 - and hetAr 2 , Ar 1 , and R 3 is as defined for formula IB. In one embodiment, ring D is substituted 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 In CH be.

[0436] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being optionally substituted with 1 to 3 fluoro. Ru, hetAr 2 C1-C6 alkyl, hetAr 2 C(=O)-, Ar1 R 3 NC(= O)-, or (C1-C6 alkyl)SO 2 - 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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)SO 2 - 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 In 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 hetAr1 C1-C3 alkyl-, hetAr 1 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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)SO 2 - 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 X4 is C It's H.

[0442] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In 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 formula 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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)SO 2- 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.

[0444] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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. Hey, hetAr 2 has 1 to 2 ring heteroatoms independently selected from N and O. A 5-6 membered heteroaryl ring having halogen, C1-C6 alkyl (1-3 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 C-H .

[0446] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with 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 ring 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: Hey, 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is (C1-C6 alkylene; RuKil)SO 2 In one embodiment, Ring D is unsubstituted. 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.

[0452] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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)SO 2 - 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 In 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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. Hey, hetAr 2 has 1 to 2 ring heteroatoms independently selected from N and O. A 5-6 membered heteroaryl ring having halogen, C1-C6 alkyl (1-3 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 C-H .

[0456] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X4 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

[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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with 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 ring 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: Hey, X 1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment, X 1 and X3 is 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 In 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; 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 In 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is (C1-C6 alkylene; RuKil)SO 2 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 , X 1 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 talisk 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. 2 C1-C6A RuKil, or hetAr 2 C(=O) and hetAr 2 is halogen and C1 -C6 alkoxy (optionally substituted with 1 to 3 fluoro) hetAr is 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 , X3 , and X 4 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 talisk 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 is 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 X4 is CH. In one embodiment, Hey, 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 talisk 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 3is N and X 2 and X 4 is CH.

[0468] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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, where E is Ar 1 N(R 3 )C(=O) and Ar 1 oh YobiR 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 1is N and X 2 , X 3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 talisk 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, hetAr 2 C1-C6 Alkyl-, or hetAr 2 C(=O) and hetAr 2 For formula IB, As defined herein. 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 , X3 , and X 4 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 talisk 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, hetAr 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 In CH Yes or X1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 talisk indicates the point of attachment to E, where E is a hetAr 2 C(=O)-, 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 talisk 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, hetAr 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4 is CH and A is CN 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 talisk 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, hetAr 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 In 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 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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 5-6 membered heteroaryl ring, which is not substituted with halogen, C1-C6 alkyl (1-3 fluorophenyl) 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, 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 In 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 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C (=O)- and hetAr 2 is as defined for formula IB. In one embodiment, ring D is unsubstituted. 2 , N 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 In 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 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; 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 In 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 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is (C1-C6 alkylene; RuKil)SO 2 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 T, 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 In 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 formula 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C 1-C6 alkyl, the alkyl portion being 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 5-6 membered heteroaryl ring, which is not substituted with halogen, C1-C6 alkyl (1-3 fluorophenyl) 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, 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 In CH Yes or X 1 and X 3 is N and X 2 and X 4is CH and A is CN and B is (hetCyc a ) C1-C3 alkyl-, hetCyc a is the formula 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is optionally substituted with a hetAr 2 C (=O)- and hetAr 2 is as defined for formula IB. In one embodiment, ring D is unsubstituted. 2 , N 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 In 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 formula 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; 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.

[0494] In one embodiment of formula IB, X 1 is N and X 2 , X 3 , and X 4 In 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 formula 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 tricyclic alkyl group indicates the point of attachment to E, and ring D is (a) a halogen atom, OH, 1-3 fluoro 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; E is (C1-C6 alkylene; RuKil)SO 2 In one embodiment, Ring D is unsubstituted. In X1 is N and X 2 , X 3 , and X 4 is CH. In one embodiment T, 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; X 1 , X 2 , X 3 , and X 4 0, 1, or 2 of are N;

[0498] A is H, CN, Cl, CH 3 -, CH 3 CH 2 -, cyclopropyl, -CH 2 C.N., or -CH(CN)CH 3 and

[0499] B is,

[0500] (a) hydrogen,

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

[0502] (c) hydroxyC2-C6 alkyl-, where the alkyl portion is a C3-C6 cycloalkyl. dihydroxy C3-C6 alkyl-, optionally substituted with an alkylidene ring;

[0503] (d) dihydroxyC3-C6 alkyl-, wherein the alkyl portion is a 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 kill-,

[0505] (f)(R 1 R 2 N) C(=O)C1-C6 alkyl-, where R 1 and R 2 Independence 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-, hetAr 1 But N, O, and S 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 1-3 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 aspartate; The Talisker 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)-, the alkyl portion being 1 to 3 Fluoro or R g R h N-substituent (wherein R g and R h are independently H or C 1-C6 alkyl), 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 SO 2 -,

[0521] (t)hetAr 2 SO 2 -,

[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 In 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 In 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. In the above formula, 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. oxy) C1-C6 alkyl.

[0534] In one embodiment of formula IC, X 2 is N and X 1 , X 3 , and X 4 In 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 In 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 pharma- ceutically acceptable salts thereof. In addition, the compounds of formula I may also be used in combination with other compounds, such as acetaminophen, ... The compounds of formula I are not necessarily pharma- ceutically 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 present invention also includes other salts of the compounds which may be used in the preparation of pharmaceutical compositions comprising the compounds of formula I, including, but not limited to, pharma- ceutically acceptable salts thereof. Typical examples are monohydrochloride, dihydrochloride, trifluoroacetate, and di-trifluoroacetate. In one embodiment, the compound of formula I is a trifluoroacetic acid and a di-salt. Contains acid salts.

[0537] The compounds of formula I or their salts may be isolated in the form of a solvate and therefore optionally 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 dissolved in water, ethanol, or other pharma- ceutically acceptable solvents. 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. In one embodiment, the compound is a phenyl group, and includes isomers and pharma- ceutically acceptable salts and solvates thereof. The compounds of Examples 1-561 are in the free base form. The compound .about.561 is the dihydrochloride and trifluoroacetate salts.

[0539] The term "pharmaceutical acceptable" refers to a compound or a salt thereof or a composition, including a formulation. and / or other ingredients and / or patients treated therewith. Indicates that the product is compatible with the following:

[0540] The compounds provided herein also include those that have a structure in which one or more of the atoms that constitute such compounds are heteroatoms. In particular, compounds according to formula I may contain unnatural proportions of atomic isotopes. When referring to a compound, the atoms are either naturally occurring or synthetically produced. 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 is understood to mean 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 Fluoro is understood to mean O or mixtures thereof. When 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 that contain 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 are illustrative of the compounds provided herein and of interest. General methods for preparing intermediates are given. For a more detailed description of the individual reaction steps, see See the Examples section below. Those of skill 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. Although shown and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives. In addition, many of the compounds prepared by the methods described below may be provided. 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, B is X 1 , X 2 , X 3 , X 4 , rings D and E are as defined for formula I.

[0543] Compound 2 was synthesized by converting commercially available 3-bromo-5-methoxypyridine (compound 1) to O-( It is obtained by treating with O-mesitylsulfonylhydroxylamine. Sulfonylhydroxylamine is prepared by the method described in 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. By crystallization or chromatographic purification, compound 4A was obtained as the minor isomer and the major isomer was obtained as the Compound 4B can be isolated by elution with POCl. 3 Process it with Compound 5 can be obtained by converting the formyl group to NH 2 OH is used to convert it to an oxime group. 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 by condensing compound 7 with aluminum trichloride. The compound can be converted to a hydroxy group by treatment with dimethylformamide to give compound 8.

[0544] To prepare compound 12 where B is hydrogen, compound 12 can be prepared by reacting compound 8 with 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 reacting under 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, Inorganic bases, such as Pd(PPh 3 ) 4 and Na 2 CO 3 (ligand in the presence of Compound 11a can be obtained by removing the protecting group P on ring D of compound 11a. 1 , Standard The Boc group can be removed by treating compound 11a with acidic conditions, e.g., HCl. (which can be removed by the addition of B) 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, such as those 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 1C1-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 formula I Each of the reagents is reacted with a reagent such as 1,2-dichlorophenyl ether (as defined for the Mitsunobu reaction condition) (e.g., PPh 3 and diisopropyl azodicarboxylate) under any protective group Compound 12 can then be converted to compound 11 by the above-mentioned reaction. It can be prepared from 11 followed by removal of the protecting groups 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-1,1-dichloromethane ester. Compound 8 is reacted with a C1-C6 alkoxy group optionally substituted with 1 to 3 fluoro groups in the presence of Kyl-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 above), hetAr 1 C1-C3 alkyl-X, (C3-C6 cycloa (hetCyc alkyl)C1-C3 alkyl-X a ) C1-C3 alkyl-X, or hetCyc a -X(where hetAr 1 and hetCyc ais 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 Protective groups (e.g., t-butyldiphenyl ether, 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 aryl group is a C1-C6 alkyl substituted aryl group, compound 9 is a C1-C6 alkyl substituted aryl group. -X, wherein the alkyl is optionally substituted with 1 to 3 fluoro, and X is B C1-C6 alkoxy groups, which are halogens such as r or Cl, or leaving groups such as triflate. Compound 11 can then be prepared by reacting it with a 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(PPh 3 ) 4 and Na 2 CO 3 Compound 9 was converted to the corresponding boronic acid ester using The compound can then be prepared by coupling with ester compound 10. Compound 12 can be 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, in which 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 B 4 is as defined for formula I; 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 to form an arbitrarily substituted 5- or 6-membered ring) to form an appropriate palladium-catalyzed chloroform. Coupling reaction conditions, for example Suzuki coupling reaction conditions (e.g., palladium catalyzed and optionally an inorganic base, such as Pd(PPh 3 ) 4 and Na 2 CO 3 (ligand in the presence of) can be used to obtain compound 14. 16 is prepared by reacting compound 14 with the appropriate S N Under Ar conditions (e.g., optionally K 2 CO 3 Bases such as and at elevated temperature), ring D is as defined for formula I, P 1 Ami The compound can be prepared by coupling with compound 15, which is a 2-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 R is H. (i.e., reacting or treating with a suitable reagent) to convert the E group to In the formula I, E is as defined above, 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) Mechanical bases, such as Pd(PPh 3 ) 4 and Na 2 CO 3 With the ligand in the presence of Compound 4A (prepared, for example, as described in Scheme 1) can be reacted with the corresponding boronic acid ester to obtain 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 three 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 is prepared by converting compound 19 to a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. 1, hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl-X, (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 above), hetAr 1 C1-C3 alkyl-X, (C3-C6 cycloalkenyl (hetCyc)C1-C3 alkyl-X 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, such as 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 is C1-C6 alkyl-X The alkyl is optionally substituted with 1 to 3 fluoro, and X is Br or Cl, etc. or a leaving group such as triflate, C1-C6 alkyl-X. Compound 20 can be prepared by removing the protecting group P on the ring D of compound 20. 1 The standard The Boc group can be removed under acidic conditions (e.g., the Boc group can be removed by treating compound 20 with acidic conditions, e.g., HCl). This can be removed by cleaving the aryl group from the aryl group, giving 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 reacted with a C1-C6 alkyl- OH, hydroxyC2-C6 alkyl-OH, optionally substituted with 1-3 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 3 and diisopropyl azodicarboxylate) to give compound 20. Compound 21 is then prepared from compound 20 as described above, followed by reaction of 20 with, 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 trimethylsilylating 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 can be reacted with an appropriate palladium-catalyzed chlo 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 Oh BiNa 2 CO 3 (ligand in the presence of Compound 10 (rings D, 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 YobiR y is H or (1-6C)alkyl, or R x and R y Is that 1 to 4 alkyl groups selected from (C1-C3 alkyl), together with the atom to which they are attached The compound is prepared by coupling with 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 reacting compound 22 with a C1- C6 alkyl-X, hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl aryl-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 formula I (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 and X is a leaving atom or group (such as a halide or triflate). and the like), each of which can be prepared by reacting with a reagent such as Each may be provided with a protecting group (e.g., t- butyldimethylsilyl group). For example, B is 1 to 3 fluoro When the compound 23 is an optionally substituted C1-C6 alkyl, the compound 23 may be replaced by C1-C6 alkyl- X, 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 with X as depicted 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 reacted with a C1-C6 alkyl- OH, hydroxyC2-C6 alkyl-OH, optionally substituted with 1-3 fluoro ( C1-C6 alkoxy)C1-C6 alkyl-X, (R1R2N)C1-C6 alkyl- OH (in the formula, R 1 and R 2is 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 3 and diisopropyl azodicarboxylate) to give compound 20. Compound 21 was then prepared from compound 20 as described in Scheme 3, followed by , if present, protecting groups on B 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 trimethylsilylating 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 reacting compound 22 with a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. 1, hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl-X, (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 above), hetAr 1 C1-C3 alkyl-X, (C3-C6 cycloalkenyl (hetCyc)C1-C3 alkyl-X 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, such as 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 is X, 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) Mechanical bases, such as Pd(PPh 3 )4 and Na 2 CO 3 (ligand in the presence of 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 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 1,2-diphenylmethane (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 directly with compound 13.

[0565] Compound 20 can be prepared by reacting compound 24 with an appropriate S N Under Ar conditions (e.g., optionally K 2 CO 3 N In the presence of any base and at high temperatures), P 1 is an amino protecting group, It can be prepared by ringing.

[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, 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 trimethylsilylating 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 reacting compound 26 with a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. 1, hydroxy C2-C6 alkyl-X, dihydroxy C3-C6 alkyl-X, (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 above), hetAr 1 C1-C3 alkyl-X, (C3-C6 cycloalkenyl (hetCyc)C1-C3 alkyl-X 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, such as 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 is X, 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 B group is methyl), 29 (wherein B group is hydrogen), and 30 (wherein the B group is excluding hydrogen) may each be prepared by a suitable palladium catalyzed cross-coupling reaction. coupling reaction conditions, e.g., Suzuki coupling reaction conditions (e.g., palladium catalyst, and optionally in dioxane at elevated temperature with an inorganic base, e.g., Pd(PPh 3 ) 4 and Na 2 CO 3 Compounds 25, 26, and 27 were synthesized using the corresponding boronic acid esters ( Stereo compound 10 (rings D, X 1 , X 2 , X 3 , and X 4 is defined as 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 three selected from (C1-C3 alkyl) By coupling with It can be prepared by the following steps.

[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. 21, where E is H. Alternatively, The resulting ring D can be functionalized (i.e., appropriately modified) to include an E group under standard conditions, such as those described below. By reacting or treating with a suitable 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 to 6 is well known to those skilled in the art. The compound can be functionalized (i.e., reacted with a suitable reagent) to contain an E group using standard chemistry available in or treated with an alkyl group, E being any one of the E groups defined for formula I, except for hydrogen; As used herein, the term "functionalized" refers to a group in which 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 any of the formulae I, I, II, III, IV, and IV, except for hydrogen. As defined in

[0574] For example, E is (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 any of OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy. (hetAr) 2 (C1-C6 alkyl)C(=O)-(alkyl part The moiety is optionally substituted with OH, hydroxyC1-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 compound 12 having ring D (i.e., compound 1 where E is hydrogen). 2) by treatment 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. 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 heterocyclic rings independently selected from N and O 5-6 membered heteroaryl ring having aryl atoms, optionally substituted -, Ar 1 (C1-C 6 alkyl)C(=O)-(alkyl portion is OH, hydroxyC1-C6 alkyl-, or C1-C6 alkoxy), hetAr 2 (C1-C6A alkyl)C(=O)-(alkyl portion is OH, hydroxyC1-C6 alkyl-, if or optionally substituted with C1-C6 alkoxy), or hetCyc 1 (C1-C 6 alkyl)C(=O)-) can be obtained. The same chemical properties can be obtained by functionalizing the 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) (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)-(alkyl part is OH, hyd. 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)- In addition, compounds 21 and 31 can be used.

[0575] Another example is when E is hetCyc 1 C(=O)- or R 3 R 4 NC(=O)- Compounds of formula I can be prepared by first deprotecting the 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 is N A saturated 4-6 membered complex having 1-2 ring heteroatoms independently selected from , O, and S. A heterocyclic ring is a ring having at least one ring N atom, and "-H" means that a hydrogen atom is present on the ring nitrogen atom. wherein the heterocycle is selected from one or more independently selected C1-C6 alkoxy substituted heterocycles. 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, E is hetCyc 1 C(=O )- or R 3 R 4 In order to prepare the compound 21 and 31, It can be used.

[0576] As another example, 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 r 1C1-C6 alkyl-, hetAr 2 C1-C6 alkyl, where the alkyl portion is optionally substituted with 1-3 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) to a C1-C6 alkyl group optionally substituted with 1 to 3 fluoro groups. Kyl-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 1C1-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] As another example, E is C1-C6 alkyl optionally substituted with 1 to 3 fluoro, (C1-C6 alkoxy)C1-C6 alkyl- optionally substituted with -3 fluoro; Ar 1 C1-C6 alkyl-, hetAr 2 C1-C6 alkyl, the alkyl portion is optionally substituted with 1 to 3 fluoro, hetAr 2 C1-C6 alkyl, hetCyc 1 C1-C6 alkyl-), the compound of formula I is deprotected compound 1 2 (i.e., E is H) can be reacted with 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( AcO) 3 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-, where the alkyl portion is 1 to Optionally substituted with 3 fluoro, hetAr 2 C1-C6 alkyl-, or h etCyc 1 Compound 12) can be obtained, which is 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 2 C1-C6 alkyl-, the Ar moiety is optionally substituted with 1 to 3 fluoro; 2 C1-C6 Alky ru- or hetCyc 1 To prepare compound 2, which is C1-C6 alkyl- Available in 1 and 31.

[0578] Accordingly, a process for preparing a compound of formula I or a pharma- ceutically acceptable salt thereof is also provided. Also provided herein are methods for treating pulmonary circulation disorders, including:

[0579] (a) E is H and A is CN, -CH 2 CN, or -CH(CN)CH 3 and 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] Compound 9, wherein B is as defined for formula I, is reacted with the corresponding compound of formula 10: A boronic 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 YobiR y is H or C1-C6 alkyl, or R x and R y Those is, together with the atom to which it is attached, 1 to 4 substituents selected from C1-C3 alkyl Form an optionally substituted 5- or 6-membered ring, 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, 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 above, the corresponding compounds of formula 14 are So, [ka]

[0585] In the formula, B, X 1 , X 2 , 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 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, a compound of formula 14, , [ka]

[0588] In the formula, L 2 is a leaving group or atom, B, X 1 , X 2 , X 3 , and X 4 But in Eq. I with a compound of formula 14, which is as defined above, [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 of formula I For compounds of formula I, the compound is of formula 18: hand, [ka]

[0591] In the formula, P 1 is an amino protecting group, and X 1 , X 2 , X 3 , X 4 and Ring D is defined as for Formula I. The compound of formula 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, 1-3 fluoro (C1-C6 alkoxy)C1-C6 alkyl optionally substituted with (R 1 R 2 N)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, E is as defined for formula I:

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

[0596] In the formula, P 1is an amino protecting group, and X 1 , X 2 , X 3 , X 4 and Ring D is defined as for Formula I. The compound of formula 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; P 1 is an amino protecting group, and X 1 , X 2 , X 3 , and X 4 is as defined for formula I to obtain 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, hydroxy C2-C6 alkyl, dihydroxy optionally substituted with fluoro hydroxyC3-C6 alkyl, optionally substituted with 1 to 3 fluoro (C1-C6 alkyl koxy)C1-C6 alkyl, (R 1 R 2 N) 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, followed by 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] The compound, wherein A is H or Cl, is reacted with 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. The corresponding boronic ester of formula 10, which forms a substituted 5- or 6-membered ring, is treated 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, and then the compound of formula 19 is obtained. 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 wherein 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 produce the corresponding A boronic 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. 10 to form a substituted 5- or 6-membered ring. , a compound of the formula [ka]

[0607] In the formula, rings D, X1 , 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 wherein rings D and E are of formula I For compounds of formula I, which are as defined above, a compound of formula 24, [ka]

[0609] In the formula, L 2 is a leaving group or atom, B, X 1 , X 2 , X 3 , and X 4 But in Eq. I with a compound of formula 24, which is as defined above, [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 , X3 , X 4 and B is of formula I 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 pharma- ceutically 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 the like, 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 protection groups for these and other protecting groups include fluoromethylphenyloxycarbonyl ("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, TW Greene, et al., Greene's Protective Groups in Organic Synthesis.N It is described in 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 according to any of the above methods may be substituted, for example, by the methods described in Greene & Wutt 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, such as those described in US Pat. No. 6,339,343, Inc., 1991. 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 have potent and selective RE For example, the compounds provided herein exhibit nanomolar inhibition of wild-type RET. showed efficacy, including KIF5B-RET fusion and V804M gatekeeper mutations, and RET mutants are selected that have minimal activity against the kinase.

[0618] In some embodiments, a compound of formula I or a pharma- ceutically acceptable salt thereof is The solvates selectively target RET kinase. For example, the compounds of formula I or A physiologically acceptable salt or solvate may have an R The ET kinase may be selectively targeted.

[0619] In some embodiments, a compound of formula I or a pharma- ceutically acceptable salt thereof is The solvate exhibits at least 30-fold selectivity for RET kinase over other kinases. For example, a compound of formula I or a pharma- ceutically acceptable salt or solvate thereof may be used in combination with another At least 40-fold selectivity for RET kinase over other kinases, 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 selectivity, at least 100-fold selectivity, at least 200-fold selectivity 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 shown. 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 determined by gating In some embodiments, the effect of the KIF keeper mutation is observed without loss of efficacy. 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 selectivity, at least 150-fold selectivity, 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 against DR.) In some embodiments, Thus, the selectivity for RET kinase over KDR kinase is approximately 30-fold. In some embodiments, the 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 a potent inhibitor of RET-targeted malonate kinase. This is thought to be a common feature among mitochondrial kinase inhibitors (MKIs), and This may be the cause of the observed dose-limiting toxicity.

[0621] In some embodiments, 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 (The IL-11 was similarly potent against V804M and V804M.) In some embodiments, another kinase Selectivity for wild-type or V804M RET kinase over ribozyme was demonstrated by enzymatic assays ( For example, enzyme assays as 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 intended to enhance the function of the brain and / or central nervous system. exhibits central nervous system (CNS) penetration. Such compounds cross the blood-brain barrier and are involved in 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 penetrating the blood-brain barrier in therapeutically effective amounts. For example, a cancer (e.g., a RET-associated cancer, such as a RET-associated brain or CNS cancer) can be treated with Treatment of a patient with the condition may include administering (e.g., orally) a compound to the patient. In such embodiments, the compounds provided herein are useful in treating primary brain tumors or metastases. These drugs are useful in treating chronic brain tumors.

[0623] In some embodiments, a compound of formula I or a pharma- ceutically acceptable salt thereof is 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-related diseases and disorders. diseases and disorders that can affect the immune system, such as proliferative disorders, including cancers, including hematological cancers and solid tumors. The present invention is useful for treating gastrointestinal disorders such as IBS, as well as chronic conditions such as bronchitis, ... and chronic obstructive pulmonary disease.

[0625] As used herein, the term "treat" or "treatment" refers to a medical condition that is 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 (i.e. not worsening) state of disease; a delayed or slowed progression of disease; 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 extending survival compared to expected survival if not receiving 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, cows, sheep, and cats. The term 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 who has been diagnosed with a disease (e.g., a disease that has been approved by a regulatory agency). as determined using a previously approved, e.g., FDA-approved, assay or kit. The RET gene, the RET protein, or its expression or activity, or The patient is identified or diagnosed as having cancer with dysregulation of any of the levels of RET (RET-associated cancer). In some embodiments, the subject is RET gene, RET protein (as determined using a previously described assay or kit) dysregulation of the quality, or expression or activity, or the level of any of them The subject may have a tumor that is positive for a tumour. the RET gene, as determined using an assay or kit approved by the Inspection of the level of RET protein, or its expression or activity, or any of them The subject may have a tumor or tumors that are positive for nodal abnormalities. Use kits or assays approved by authorities, e.g., approved by the FDA. The tumor is identified as having a gene, protein, or The subject may have a dysregulation of 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. The present invention relates to a method for treating a tumor having a dysregulation of the expression or activity of and optionally, the clinical records indicate that the subject is In some embodiments, the composition may be one of the following: and 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 "pediatric" refers to patients with to 2 years old), Children (2 to 12 years old), Adolescents (12 to 21 years old (22 years old) The exposure can be divided into various subpopulations, including those up to but not including the birthday of 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 case, pediatric patients were classified as those from birth to 28 days after birth, those from 29 days after birth to under 2 years of age, and those from 2 years of age to 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 the 29th 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, the 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 to prevent, 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 associated with the RET 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 Any of the types of dysregulation of expression or activity or level of any of those described. or) is associated with dysregulation of the expression, activity, or level 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 an attack of the RET gene, 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] "The RET gene, the RET kinase, or the expression or activity or The phrase "dysregulation of levels of a gene" refers to a genetic mutation (e.g., a gene that causes expression of a fusion protein) that is RET gene translocation, a deletion of at least one amino acid compared to the wild-type RET protein A deletion in the RET gene that results in expression of a RET protein containing the deletion, at least one point Mutations in the RET gene that result in expression of a mutated RET protein or is a deletion 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 ​​versions, or an excess of RET protein Amplification of the RET gene leading to expression or the kinase domain of the RET protein in cells The pathogenic role 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 that results in increased As another example, the RET gene, the RET protein, or their Any dysregulation of 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 RET gene may be a mutation in the RET protein having the following structure: The RET gene, the RET protein, or the expression or activity of any of them 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) In some instances, the RET gene may be the result of a genetic or chromosomal translocation that results in , RET protein, or modulation of expression or activity or levels 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) that can be used to treat a RET inhibitor-resistant cancer include RET inhibitor-resistant mutations. Non-limiting examples of drug resistance mutations are listed in Tables 3 and 4.

[0632] The term "wildtype" or "wild-type" means , do not have a RET-associated disease, e.g., a RET-associated cancer (and optionally, do not have a RET-associated disease, e.g., a RET-associated cancer) 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 in cells or tissues from subjects (not suspected of having a RET-related disorder) , a nucleic acid (e.g., a RET gene or a RET mRNA) or a protein (e.g., a RET gene or a RET mRNA) ET protein).

[0633] The term "regulatory body" refers to the regulatory 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 (eg, 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 pharma- ceutically acceptable salt or 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) detecting an expression of the RET gene, RET kinase, or any of them in a sample from a patient; and b) detecting dysregulation of expression or activity or level of a compound of formula I. or a pharma- ceutically acceptable salt or solvate thereof, Methods are provided herein. In some embodiments, the RET gene, RET kinase, Dysregulation of the expression or activity or level of any of the Non-limiting examples of RET gene fusion proteins are listed in Table 1. In some embodiments, the fusion protein is In some embodiments, the RET gene, RET kinase, or any of them Dysregulation of the expression or activity or levels of one or more RET kinase proteins RET kinase protein point mutations / insertions / deletions Non-limiting examples of RET kinase are listed in Table 2. The point mutations / insertions / deletions in the enzyme protein were M918T, M918V, C634W, and V8 In some embodiments, the compound of formula Compounds 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 3 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 pharma- ceutically 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 any of the above, the cancer (e.g., RET-associated cancer) is a solid tumor. In some embodiments of any of the methods or uses described herein, The cancer (e.g., RET-associated cancer) may be lung cancer (e.g., small cell lung cancer or non-small cell lung cancer), thyroid cancer, or ovarian cancer. Thyroid adenocarcinoma (e.g., papillary thyroid carcinoma, medullary thyroid carcinoma, differentiated thyroid carcinoma, recurrent thyroid carcinoma, if (or refractory 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 carcinoma. 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), and L), adolescent cancer, adrenocortical cancer, anal cancer, appendiceal cancer, astrocytoma, atypical teratoma / rhabdoidoma tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchial tumor, Kitten's lymphoma, carcinoid tumor, cancer of unknown primary site, cardiac tumor, cervical cancer, childhood cancer, notochord Myeloma, 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 and chest 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 neuroendocrine tumor Secretory tumors, Kaposi's sarcoma, renal 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, multilineage 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 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 cancer (oral cavity c ancer), lip cancer, oral and pharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, Paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary cancer, plasmacytoma tumors, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system lymphoma, primary peritoneal cancer, prostate cancer , rectal cancer, colon cancer, colon cancer neoplasms, 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 myelogenous 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 (MPDs) 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 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 black 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, thyroid adenocarcinoma, refractory differentiated thyroid cancer, and multiple endocrine neoplasia type 2A or 2B (respectively, ME N2A or MEN2B), pheochromocytoma, parathyroid hyperplasia, breast cancer, colorectal cancer, papillary nephropathy The cancer is selected from the group consisting of gastrointestinal mucosal ganglioneuroma, and cervical cancer.

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

[0640] The compounds of formula I and their pharma- ceutically acceptable salts and solvates are also useful in the treatment of RET-associated cancers. They are also useful for treating

[0641] Thus, RET-associated cancers, such as any of the exemplary RET-associated cancers disclosed herein, A method for treating a patient diagnosed or identified as having any of the following, comprising administering to the patient a therapeutically effective amount of or a pharma- ceutically 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, the 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 RET gene, or any of them The defect may be a translocation or overexpression of the RET kinase, the RET gene, or the RET kinase domain. The translocation may be inactivated, activated, amplified, or mutated. 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, which may also contribute to tumorigenesis.

[0643] In some embodiments, the RET gene, the RET kinase, or any of them. The dysregulation of expression, activity or level of RET kinase is due to overexpression of wild-type RET kinase ( In some embodiments, the RET gene is or the expression or activity or receptor of any of them. Dysregulation of the bell may indicate, for example, a kinase domain portion or kinase activity. overexpression in a chromosomal segment that contains 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 Dysregulation of the expression, activity or level of any of these genes is caused by RET gene fusion. In some embodiments, the RET gene is a chromosomal translocation or inversion. or the expression or activity or receptor of any of them. Dysregulation of RET is due to the fact that expressed proteins incorporate residues from non-RET partner proteins. A fusion protein comprising a RET kinase domain and 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 any of them. The dysregulation of expression, 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 any of them Dysregulation of expression, activity or levels of the RET kinase domain results in constitutive activity of the RET kinase domain. The deletion of one or more residues from the RET kinase results in

[0648] In some embodiments, the RET gene, the RET kinase, or any of them. Dysregulation of the expression or activity or level of, 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 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 any of them. Dysregulation of the expression or activity or level of, 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., (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 any of them. The dysregulation of expression, activity or level of RET mRNA is due to splicing The RET kinase domain contains a mutation that results in constitutive activity of the RET kinase domain (wild type RET Selective sequencing of RET having 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 the concentration is less than about 1000 nM, less than about 500 nM, less than about 200 nM, or 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. 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 a "first RET inhibitor " is a RET kinase inhibitor as defined herein, but having formula I as defined herein. or a pharma- ceutically acceptable salt or solvate thereof. A "second RET kinase inhibitor" or a "second RET inhibitor" as used herein is defined as a A RET kinase inhibitor as defined herein, but of formula I or a compound thereof as defined herein. The present invention does not include pharma- ceutically 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 any of them. Dysregulation of the expression or activity or level of, as compared to wild-type RET kinase, RET kinases having one or more amino acid insertions or deletions, RET kinase having one or more amino acid substitutions or insertions or deletions in the gene Optionally, the RET gene contains at least one point mutation that results in the production of Thus, the resulting RET kinase may be a wild-type RET kinase or one containing the same mutation. one or more first RET kinase inhibitors (multiple inhibitors) Such mutations are more resistant to inhibition of their phosphotransferase activity by Optionally, the compound of formula I or a pharma- ceutical acceptable salt or solvate thereof may be used in the treatment of does not reduce the sensitivity of cancer cells or tumors that have RET kinase to therapeutic agents (e.g., (compared to cancer cells or tumors that do not contain the specific RET inhibitor resistance mutation). In some cases, RET inhibitor resistance mutations may occur in wild-type RET kinase or in the same first RET The first RET kinase is compared to a RET kinase that does not have the same mutation in the presence of a kinase inhibitor. In the presence of a kinase inhibitor, 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 any of the expression vectors thereof is Dysregulation of expression, activity or levels of RET kinase in one or more This results in the production of RET kinases having the above amino acid substitutions, or a RET kinase not containing the same mutation, A small mutation in the RET gene that confers increased tolerance to a naturally tolerated salt or solvate. In such an embodiment, the RET inhibitor-resistant mutation is a compound of formula I or a pharma- ceutically acceptable salt thereof, In the presence of a solvate, a compound of formula I or In the presence of a pharma- ceutically acceptable salt or solvate thereof, V max Increase in K m Decrease in and K. D The method may 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 within and near the motif, as well as the ATP cleft solvent front amino acid residues, are included. In particular, but not limited to, within 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 of such residues include residues in the activation loop, residues near or interacting with the activation loop, Enzyme residues, including but not limited to those 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 non-limiting examples of RET inhibitor resistance mutation positions are shown in Table 4. These residues 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 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 VGGHEPGEPR 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 pharma- ceutically acceptable salts and solvents The compound may be administered in combination with existing drug therapies (e.g., other REs). T kinase inhibitors, e.g., a first and / or a second RET kinase inhibitor or as follow-up therapy for RET inhibitor resistance mutations (e.g., increased resistance to, e.g., amino acid position 804, e.g., V804M, V804L, or V804E, and / or one or more of the RET These compounds are useful in treating patients who develop cancers that have a mutation in a gene that causes resistance to ribosome inhibitors. The first and second RET kinase inhibitors are described herein. In one 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, the compound of formula I or a pharma- ceutically acceptable salt and solution thereof is The mediator may be (e.g., increased resistance to first and second RET inhibitors, e.g., amino resulting in a substitution at acid position 804, e.g., V804M, V804L, or V804E. (b) is 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 first arose in thyroid follicular cells and is the most common cause of 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) A somatic chromosomal rearrangement (translocation or inversion) that links a constitutively expressed 5' segment Such rearrangements may promote the ectopic expression of thyroid gland proteins 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 with RET is known to be involved in the transcriptional regulation of IFN-γ expression, but the fusion of RET / PTC3 and RET / PTC4 is known to be involved in the transcriptional regulation of IFN-γ expression. Fusion events resulting in different proteins with different molecular weights (e.g., F Ugazzola et al., Oncogene, 13(5):1093-7,19 96). Several RET fusions associated with PTC are referred to as "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 (see oi:10.3389 / fendo.2012.00054,2012). The role of RET-PTC rearrangements in the pathogenesis of PTC was investigated in transgenic mice. It has been confirmed (Santoro et al., Oncogene, 1996, 12 To date, various fusion partners have been identified in PTC and other cancer types. have been identified, all of which demonstrate 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. Intric inversions have been identified in approximately 2% of lung adenocarcinoma patients, and the chimeric gene KIF5B -Ret gene variants (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 expressed the N-terminal coiled-coil domain of KIF5B, which mediates homodimerization. The RET kinase domain is a subset of the RET kinase domains. do not have oncogenic alterations (EGFR or K-Ras mutations, ALK translocations, etc.), which is These results 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, similar to what has been confirmed with the RET-PTC fusion protein. KIF5B-RET is constitutively phosphorylated and mediates 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-1 protein, have been identified in patients with lung adenocarcinoma. was 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 for the treatment of lung cancers that contain RET rearrangements. It has been shown that there is l 33, 2015(suppl;abstr 8007)). RET fusion proteins It has also been identified in patients with colorectal cancer (Song Eun-Kee, 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 MTCs are 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 hereditary cancer syndromes. In subtypes (MEN2A, MEN2B, and familial MTC / FMTC), RE T gene mutations are strong phenotypic and genetic variables that define 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, and is ligand-independent. This leads to dependent homodimerization and constitutive RET activation. Patients are diagnosed at a young age (5–25 years). MTC develops in patients with pheochromocytoma (50%) and hyperparathyroidism. MEN2B is primarily characterized by the M918T mutation located within the kinase domain. This mutation renders RET constitutively active in its monomeric state, Alters substrate recognition by kinases. MEN2B syndrome is characterized by early onset (<1 year) and highly aggressive forms of MTC, pheochromocytoma (50% of patients) and ganglioneuroma. In FMTC, the only disease manifestation is MT progression, which usually occurs in adulthood. C. Many different mutations have been detected throughout the RET gene. The remaining 75% of cases are sporadic, and about 50% of them have somatic RET mutations. The most frequent mutation, M918, is associated with the most aggressive phenotype, similar to MEN2B. Somatic point mutations in RET have also been implicated in colorectal cancer (Wood et al., 2003). science, 2007, 318, 1108-13) and small cell lung cancer (Jpn. JC In other tumors such as 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 of this type (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., 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 demonstrated in patients with colorectal cancer (PDX) The frequency of such events in patients with colorectal cancer remains unknown. Although not specifically identified, these data support the use of RE as a target in this indication. This suggests 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 found in 5–10% of cases. RET has been identified in a number of cases, demonstrating its role in sporadic colon cancer. These results suggest that the IL-1 gene 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 that can affect tumor progression and spread. RET is expressed in 50-65% of pancreatic cancers. 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 Rare chromosomal rearrangements involving RET have 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. toward the monocyte pathway, possibly by initiation of RET-mediated RAS signaling. (Ballerini, P., et al., Leukemia, 2012, 26 ,2384-2389).

[0668] RET expression is also found in a number of 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 neurotrophin receptors downregulating N-Myc, potentially in cooperation with NF-κB, and may play 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, et al. 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 pharma- ceutical acceptable salt thereof. The present invention relates to a method for treating cancer, the method comprising administering to a patient diagnosed with cancer (or suspected of having cancer) a Provided herein is a method for treating a patient (defined as a patient having a pulmonary circulation disorder) comprising administering to the patient a therapeutically effective amount of administering a compound of formula I or a pharma- ceutically acceptable salt or solvate thereof or a pharmaceutical composition and administering to a patient identified or diagnosed with a RET-associated cancer a Methods are also provided herein. In some embodiments, the patient or or 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 A regulatory agency approved method for identifying dysregulation of expression or activity or level of A test or assay that has been approved, e.g., FDA-approved, to identify a patient with a RET-associated cancer In some embodiments, the test or assay comprises: 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] 1. A method for treating cancer in a patient in need of such treatment, comprising: (a) administering to the patient (b) determining whether the cancer is a RET-associated cancer; and If so, administering to the patient a therapeutically effective amount of a compound of formula I, or a pharma- ceutical acceptable salt thereof. or a solvate, or a pharmaceutical composition thereof. Some embodiments of these methods include administering to the subject another anti-cancer agent (e.g., a second RE a T inhibitor, a second compound of formula I or a pharma- ceutically acceptable salt or solvate thereof, and In some embodiments, the subject further comprises administering a first Previously treated with a RET inhibitor or other anti-cancer treatment, e.g., tumor resection In some embodiments, the patient has been previously treated with radiation therapy. or in a biopsy sample from a patient thereof, or in the assays described herein, By carrying out any of the above-mentioned examples, the RET gene, RET kinase, or A regulatory protein for identifying abnormalities in the expression or activity or level of any of RET-related mutations were detected using a regulatory 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 an abnormality in the RET gene, RET kinase, or expression or activity of either of them. A sample obtained from the patient is subjected to a test to determine whether the patient has a dysregulated level of conducting an assay and administering a therapeutically effective amount of a compound of formula I or a pharma- ceutically acceptable salt thereof to a subject; The present invention relates to a method for treating a RET gene, a RET kinase, or a compound comprising administering the same to a patient having ... the same. or any of the expression, activity, or level thereof is determined to be abnormal. and administering (e.g., specifically or selectively administering) the compound to a patient. Methods for treating rheumatoid arthritis are also provided. Some embodiments of these methods include administering to a subject another an anti-cancer agent (e.g., a second RET inhibitor, a second compound of Formula I or a pharma- ceutically acceptable derivative thereof); These methods further include administering to the subject a therapeutically effective amount of a compound selected from the group consisting of a compound comprising a medicament for treating a disease, 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 the like. In some embodiments, the method utilizes sequencing, immunohistochemistry, or degradative FISH analysis. In the present study, the assay is a regulatory agency approved assay, e.g., an FDA approved assay. Additional non-limiting assays that can be used in these methods are described herein. Additional 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, the 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, The gene, RET kinase, or the expression or activity or level of any of them To determine whether a patient has a dysregulation, an assay ( The patient is identified as having a RET-associated cancer through, for example, performing an in vitro assay. The present invention relates to a compound of formula I or a pharmaceutical composition thereof for use in treating a RET-associated cancer in a patient diagnosed with or having a retinopathy of interest. Also provided are therapeutically 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 any of the expression or activity or levels thereof. An assay is performed on a sample obtained from a patient to determine whether the patient has a mutation. The present invention relates to a method for identifying and / or diagnosing a RET-associated cancer in a patient who is identified or diagnosed with a RET-associated cancer through the steps of: The present invention relates to a compound of formula I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for treating cancer. Use of the salt or solvate thereof in the methods or uses described herein is also provided. Some embodiments of any of these include, but are not limited to, those in which the patient has a gene, a gene encoding a RET gene, a RET kinase, or a gene encoding a RET kinase. The patient has been determined to have abnormal regulation of the expression, activity or level of any of these. and recording the result in a patient's clinical record (e.g., in a computer readable medium), Through the practice of the present invention, a compound of formula I or a pharma- ceutically acceptable salt or solvate thereof, In some embodiments, the assay comprises administering to the subject a pharmaceutical composition comprising the subject 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 is an assay that is approved by the FDA. T gene, RET kinase, or the expression or activity or level of any of them Dysregulation of RET includes one or more RET inhibitor resistance mutations.

[0675] In patients in need of treatment or identified or diagnosed with RET-associated cancer A compound of formula I or a pharma- ceutically acceptable salt or Solvates are also provided. The present invention relates to a compound of formula I or a pharma- ceutical acceptable salt thereof for the manufacture of a medicament for treating cancer. Use of a salt or solvate 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 is diagnosed with a RET The RET gene, RET kinase, or the expression or activity or reactivity of any of them Regulatory agency approved, e.g., FDA approved, to identify bell dysregulation The subject has 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, the RET kinase, or the expression or activity or reactivity of either of them 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, , 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 any of them. have a 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 some cases, the patient has 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 is diagnosed with a RET-associated cancer (e.g. For example, cancers 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 pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the RET gene, RE Dysregulation of the expression or activity or levels of T kinase, or any of them, Non-limiting examples of RET gene fusion proteins are listed in Table 1. In some embodiments, the fusion protein comprises a KIF5B-RE In some embodiments, the RET gene, RET kinase, or the like is T. Dysregulation 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 / Non-limiting examples of insertions / deletions are described 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 resin is selected from the group consisting of V804W, V804L, and V804M. The RET gene, the RET kinase, or the expression or activity of either of them in The dysregulation of RET levels includes 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 serotonin, RET kinase, or any of them The cancer having the abnormality may be assayed using a regulatory approved, e.g., FDA approved, assay or is determined using a kit. In some embodiments, the RET gene, RETkinase or dysregulation of the expression, activity, or levels of any of them. A tumor that is prognostic 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 a therapeutic agent approved by a regulatory agency, 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 present invention relates to a method for treating a patient having a deficiency in the RET gene, RET kinase, or the expression or activity of either of them. Tumors with dysregulated RET expression or levels (e.g., harboring 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 step of administering to the patient a compound of formula I or a pharma- ceutically acceptable salt or solvate thereof, Indicating 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 or activity or levels of RET are characterized by one or more RET inhibitor-resistant mutations. In some embodiments, the cancer has a mutation in the RET gene, RET kinase, or Cancers that have dysregulation of the expression or activity or levels of any of these Determined using an assay or kit approved by an agency, 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 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 pharma- ceutical acceptable salt thereof to a patient. The RET gene, RET kinase, or a salt or solvate thereof may be administered to a patient. Have clinical records showing dysregulation of any expression, activity or level Also provided is a method of administering to a patient having a RET gene, a RET inhibitor, or a combination thereof. T kinase, or any of their expression or activity or levels are dysregulated. Manufacture of a medicament for treating RET-associated cancer in a patient with clinical records indicating that The use of a compound of formula I or a pharma- ceutically acceptable salt or solvate thereof for Some embodiments of these methods and uses include a method for detecting a patient-derived sample. to determine whether a patient has a RET gene, RET kinase, or either of these determining whether the patient has a dysregulation of expression or activity or level of The person has an abnormality in the RET gene, RET kinase, or any of their expression or activity or The clinical files (e.g., computerized) of patients identified as having dysregulation of the blood glucose level were used to The method may further include recording the information on a computer-readable medium. In embodiments, the assay is an in vitro assay. For example, next generation sequencing. Assays utilizing immunohistochemistry, immunohistochemistry, or degradative FISH analysis. In some embodiments, the assay is approved by a regulatory agency, e.g., an FDA approved kit. In some embodiments, the RET gene, RET kinase, or the like is Dysregulation of the expression, activity or level of one or more RET inhibitors is associated with resistance to RET inhibitors. Includes sexual variation.

[0679] Also provided herein are methods of treating a subject, the methods comprising administering to a sample obtained from the subject Assays can be performed to determine whether a subject has a RET gene, RET protein, or both. This method includes determining whether the expression or level of any of the The methods also include detecting the RET gene, the RET protein, or the expression or activity of either thereof. a subject determined to have a dysregulation of the sex or level of or a pharma- ceutically acceptable salt or solvate thereof. In some embodiments, the RET gene, the RET kinase protein, or their expression or The dysregulation of activity can be caused by a RET fusion protein (e.g., any of the RET fusion proteins described herein). A gene or chromosomal translocation that results in the expression of a fusion protein (either a fusion protein or a fusion protein). In an embodiment, the RET fusion is a KIF5B-RET fusion and a CCDC6-RET fusion. In some embodiments, the RET gene, RET fusion gene, T kinase proteins, or the expression or activity or level of any of them The nodal abnormality may be caused by one or more point mutations in the RET gene (e.g., a point mutation described herein). The RET gene is a genetic mutation that occurs when one or more of the following point mut...

Claims

1. Formula 12: 【Chemistry 1】 A method for producing a compound of the formula: Formula 16: 【Chemistry 2】 and deprotecting the compound of formula (I) In the above formula, P １ is an amino protecting group, B, (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro; (c) hydroxyC2-C6 alkyl-, wherein the alkyl moiety is optionally substituted with 1 to 3 fluoro or C3-C6 cycloalkylidene rings; (d) dihydroxyC3-C6 alkyl-, wherein the alkyl moiety 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 the alkyl portion is optionally substituted with OH; R １ and R ２ is independently H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro); 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 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 each of said C1-C4 alkyl and C1-C6 alkyl moieties is 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 is independently H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro); 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, X １ , X ２ , X ３ , and X ４ are independently CH, CF, CCH ３ or N, X １ , X ２ , X ３ , and X ４ is N; Ring D is (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, (ii) a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, each of said rings being optionally substituted with 1-4 groups independently selected from (a) halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or C1-C3 alkoxy optionally substituted with 1-3 fluoro, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; The process for producing wherein E is (a) hydrogen.

2. The P １ 2. The method of claim 1 , wherein: is a Boc group, and deprotecting the compound of formula 16 comprises treating the compound of formula 16 with an acid.

3. Formula 12: 【Chemistry 3】 wherein E is a functional group, comprising the steps of: Formula 12: 【Chemistry 4】 (wherein E is hydrogen), In the above formula, B, (a) hydrogen, (b) C1-C6 alkyl optionally substituted with 1 to 3 fluoro; (c) hydroxyC2-C6 alkyl-, wherein the alkyl moiety is optionally substituted with 1 to 3 fluoro or C3-C6 cycloalkylidene rings; (d) dihydroxyC3-C6 alkyl-, wherein the alkyl moiety 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 portion is optionally substituted with OH and R 1 and R 2 are independently H or C1-C6 alkyl (optionally substituted with 1 to 3 fluoro); (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 is optionally substituted with one or more independently selected C1-C6 alkyl substituents; (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 each of said C1-C4 alkyl and C1-C6 alkyl moieties is 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); 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; X 1 , X 2 , X 3 , and X 4 are independently CH, CF, CCH 3 , or N, and 0, 1, or 2 of X 1 , X 2 , X 3 , and X 4 are N; Ring D is (i) a saturated 4-7 membered heterocyclic ring having two ring nitrogen atoms, (ii) a saturated 7-9 membered bridged heterocyclic ring having two ring nitrogen atoms and optionally having a third ring heteroatom which is oxygen, (iii) a saturated 7-11 membered heterospirocyclic ring having two ring nitrogen atoms, or (iv) a saturated 9-10 membered bicyclic fused heterocyclic ring having two ring nitrogen atoms, each of said rings being optionally substituted with 1-4 groups independently selected from (a) halogen, OH, C1-C3 alkyl optionally substituted with 1-3 fluoro, or C1-C3 alkoxy optionally substituted with 1-3 fluoro, (b) a C3-C6 cycloalkylidene ring, or (c) an oxo group; The functional group is (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 selected from 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 portion 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; 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 -, wherein the alkyl moiety is optionally substituted with 1 to 3 fluoro, (C1-C6 alkyl)SO 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 -, 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 optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoro), C1-C6 alkoxy (optionally substituted with 1-3 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 5-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O; hetAr 2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O, and S, or a 9-10 membered bicyclic heteroaryl ring having 1-3 ring nitrogen atoms, and hetAr 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoro), C1-C6 alkoxy (optionally substituted with 1-3 fluoro), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 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; The process for preparation wherein R 4 is C1-C6 alkyl.

4. The method of any one of claims 1 to 3, wherein B is hydroxy C2-C6 alkyl-, said alkyl moiety optionally substituted with 1 to 3 fluoro or C3-C6 cycloalkylidene rings.

5. 5. The method of claim 4, wherein B is hydroxy C2-C6 alkyl-, wherein the alkyl moiety is unsubstituted.

6. B is of the formula: 【Chemistry 5】 The method of claim 4, wherein the compound is selected from the group consisting of:

7. The method of any one of claims 1 to 3, wherein B is C1-C6 alkyl optionally substituted with 1 to 3 fluoro.

8. The method of any one of claims 1 to 3, wherein B is methyl, ethyl, propyl, isopropyl, isobutyl, 2-methylbutyl, 2-ethylbutyl, 2,2-dimethylpropyl, difluoromethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl.

9. The method of any one of claims 1 to 8, wherein Ring D is a saturated 7-9 membered bridged heterocyclic ring having 2-3 ring heteroatoms independently selected from N and O.

10. Ring D and E moieties of formula 12: 【Chemistry 6】 is expressed by the following formula: 【Chemistry 7】 The method according to any one of claims 1 to 8, wherein the compound is selected from the group consisting of:

11. Ring D is of the following formula: 【Chemistry 8】 and In the formula, the wavy line represents X １ , X ２ , X ３ , and X ４ and an asterisk indicates the point of attachment to E.

12. Ring D and E moieties of formula 12: 【Chemistry 9】 is expressed by the following formula: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 The method of claim 3, wherein the compound is selected from the group consisting of:

13. The following formula: 【Chemistry 14】 A method for producing a compound of the formula: 【Chemistry 15】 The compound of NaBH(OAc) ３ with 6-methoxynicotinaldehyde in the presence of

14. 14. The method of claim 13, wherein the reaction is carried out in a solvent of dichloroethane.

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