Compound used as thyroid hormone receptor agonist

Abstract

The present invention provides compounds of Formula (I) or (1a), or tautomers or pharmaceutically acceptable salts thereof, and also provides compounds of Formulae (II) to (V), or tautomers or pharmaceutically acceptable salts thereof. These compounds and pharmaceutical compositions containing them are useful in the treatment of diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, as well as other related conditions and diseases, and are useful in other diseases such as NASH, e.g., NASH, etc. , atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, and other related conditions and diseases. # imgabs0 #

Description

[0001] This application is a divisional application of the invention application with an application date of February 20, 2020, application number 202080015099.6, and invention name “Novel compounds and their use as thyroid hormone receptor agonists”. Background of the Invention 1. Technical Field

[0003] The present invention relates to novel thyroid hormone receptor agonists. The present invention also relates to the use of such compounds in the treatment of metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes and other diseases such as NASH (non-alcoholic steatohepatitis), hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases. 2. Background technology

[0004] Thyroid hormones are hormones produced and released by the thyroid gland. They are primarily responsible for regulating metabolism and are essential for normal growth and development and for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms via the hypothalamus / pituitary / thyroid (HPT) axis. They also have profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle, and behavior.

[0005] The biological activity of thyroid hormones is mediated by thyroid hormone receptors (TRs). TRs belong to a superfamily known as nuclear receptors. TRs form heterodimers with retinoid receptors, which are ligand-induced transcription factors. TRs have a ligand-binding domain, a DNA-binding domain, and an amino-terminal domain. TRs regulate gene expression by interacting with DNA response elements and various nuclear coactivators and co-repressors. TRs come from two independent genes, α and β, and can be further classified into TRα1, TRα2, TRβ1, and TRβ2. Among them, thyroid hormone receptors α1, β1, and β2 can bind to thyroid hormones. Different subtypes of TRs contribute differently to specific biological responses. For example, TRβ1 plays an important role in regulating TRH (thyrotropin-releasing hormone) and regulating the effects of thyroid hormones in the liver; TRβ2 plays an important role in the regulation of TSH (thyroid-stimulating hormone) (Abel et al. J. Clin. Invest., Vol 104: pp. 291-300 (1999)).

[0006] Recent studies have shown that the appropriate use of thyroid hormones can produce some beneficial therapeutic effects. For example, thyroid hormones increase metabolic rate, oxygen consumption, and heat production, thereby reducing weight. Weight loss will have a beneficial effect on obese patients and may also have a beneficial effect on glycemic control in obese patients with type 2 diabetes.

[0007] Other therapeutic benefits of thyroid hormones include lowering low-density lipoprotein (LDL), increasing hepatic LDL receptor expression, stimulating the metabolism of cholesterol to bile acids, increasing HDL cholesterol, and increasing the LDL-to-HDL ratio. Thyroid hormones may also reduce the risk of atherosclerosis and other cardiovascular diseases.

[0008] As the incidence of obesity and its complications, diabetes, metabolic syndrome, and atherosclerotic vascular disease rises at epidemic rates, the utility of compounds that can treat these diseases will be greatly desired. To date, the therapeutic use of naturally occurring thyroid hormones has been limited by the adverse side effects associated with hyperthyroidism, especially cardiovascular toxicity.

[0009] Therefore, efforts have been made to synthesize thyroid hormone analogs that exhibit increased TRβ selectivity and / or tissue-selective effects. Such thyroid hormone mimetics may produce the desired reduction in body weight, lipids, cholesterol, and lipoproteins while reducing effects on cardiovascular function or the normal function of the hypothalamic / pituitary / thyroid axis.

[0010] For example, WO2001060784A1 discloses aniline-derived ligands of the following formula for use in thyroid receptors,

[0011]

[0012] wherein X is -O-, -S-, -CH2-, -CO-, or -NH-; Y is -(CH2)n-, wherein n is an integer from 1 to 5, or cis- or trans-ethylene; R1 is halogen, trifluoromethyl, or an alkyl group of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 7 carbon atoms; R2 and R3 are the same or different and are hydrogen, halogen, an alkyl group of 1 to 4 carbon atoms or a cycloalkyl group of 3 to 6 carbon atoms, and at least one of R2 and R3 is not hydrogen; R4 is hydrogen or a lower alkyl group; R5 is hydrogen or a lower alkyl group; R6 is a carboxylic acid or an ester or a prodrug; R7 is hydrogen or an alkanoyl group or an aromatic acyl group.

[0013] WO2007009913A1 discloses pyridazinone derivatives of the following formula as thyroid hormone receptor agonists:

[0014]

[0015] wherein A is O, CH2, S, SO or SO2; X and Y are each independently selected from Br, Cl and -CH3; R 1 Selected from -(CH2)nCOOH; -OCH2COOH; -NHC(=O)COOH; -NHCH2COOH; Z is H, or -C≡N; R 2 is a lower alkyl group; R 3is H or lower alkyl; n is 1, 2 or 3; p is 1 or 2; or a pharmaceutically acceptable salt or ester thereof.

[0016] WO2009037172A1 discloses pyridazinone derivatives of the following formula as prodrugs of thyroid hormone analogs:

[0017]

[0018] Among them, R 1 Is -OH, O-linked amino acid, -OP(O)(OH)2 or -OC(O)-R 2 ; R 2 is lower alkyl, alkoxy, alkyl ether, cycloalkyl, heterocycloalkyl, -(CH2)n-heterocycloalkyl, aryl, heteroaryl, or -(CH2)n-heteroaryl; and n is 0 or 1; or pharmaceutically acceptable salts and esters thereof.

[0019] WO2010122980A1 discloses the following formula as a thyroid hormone receptor agonist,

[0020]

[0021] wherein A is optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted carbamoyl, X is optionally substituted methylene, -O- or -S-, and Q is N or CR 4 , L 1 It is a single bond, methylene, -CH=CH-, -O-, -CO-, -NR 11 -,-NR 11 CO-,-CONR 11 -, -CH2NR 11 -or-S-,L 2 It is a single bond, -CR 6 R 7 -, or a divalent heterocyclic group, R 1 and R 2 are the same or different, each being hydrogen, alkyl, alkenyl or halogen, R 3 and R 4 are the same or different, each being hydrogen, alkyl, alkoxy, cyano or halogen, R 1 and R 3 optionally combined to form a carbocyclic or heterocyclic ring, R 5 is a carboxyl group, an alkoxycarbonyl group, or a bioisostere of a carboxyl group, R 6 and R 7 are the same or different and are each hydrogen, optionally substituted alkyl or halogen, or R 6 and R 7 Bonded to form cycloalkanes or heterocycles, R8 is hydroxy, alkanoylamino or alkylsulfonylamino, R 9 and R 10 are the same or different, each being hydrogen, alkyl or halogen, and R 10 is hydrogen or alkyl, or a pharmaceutically acceptable salt thereof.

[0022] The development of thyroid hormone analogs that avoid the adverse effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormone will open new treatment avenues for patients with metabolic diseases (e.g., obesity, hyperlipidemia, hypercholesterolemia, diabetes) and other diseases (e.g., hepatic steatosis and NASH, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer, thyroid disease), and related conditions and diseases.

[0023] The problem of metabolic diseases continues to increase, and the current lack of safe and effective drug treatments highlights the urgent need for new THR agonist drug treatments without adverse effects. Summary of the invention

[0024] The technical problem to be solved by the present invention is to provide a novel thyroid receptor agonist, which can be used to treat metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, and can also be used to treat other diseases such as NASH, hepatic steatosis, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases.

[0025] In order to solve the above technical problems, the present invention adopts the following technical solutions.

[0026] In one aspect, provided herein is a compound of formula (I) or (Ia), or a tautomer or a pharmaceutically acceptable salt thereof,

[0027]

[0028]

[0029] A is O or CH2;

[0030] B is N or CH;

[0031] X is O or NR 1 or CHR 1 ;

[0032] R 1 is selected from a bond or H or lower alkyl;

[0033] R 2 is H or lower alkyl;

[0034] or R 1 and R 2Together with the X-C=C to which they are attached, they form a 5- to 9-membered carbocyclic or heterocyclic ring which is unsubstituted or replaced by R 6 and R 7 Replacement, R 6 and R 7 Independently selected from H or lower alkyl;

[0035] R 3 and R 4 Independently selected from H, F, Cl, Br and CH3;

[0036] R 5 Selected from:

[0037]

[0038] A compound of formula (I) or (Ia), wherein B is CH;

[0039] More preferably, wherein A is CH2;

[0040] More preferably, wherein X is O, R 2 It is a lower alkyl group.

[0041] More preferably, wherein R 2 It is isopropyl.

[0042] More preferably, wherein R 3 and R 4 Independently selected from F, H, Cl or CH3.

[0043] More preferably, wherein R 5 yes

[0044] A compound of formula (I) or (Ia) wherein B is CH and A is O.

[0045] More preferably, wherein R 5 yes

[0046] More preferably, wherein X is NR 1 or CHR 1 , R 1 and R 2 Together with the X-C=C to which they are connected, they form a 5-membered heterocyclic ring, namely:

[0047]

[0048] R 6 and R 7 Independently selected from H or CH3.

[0049] More preferably, wherein R 3 and R 4Independently selected from F, H, Cl, CH3.

[0050] A compound of formula (I) or (Ia), wherein B is N.

[0051] More preferably, wherein R 5 yes

[0052] More preferably, wherein R 3 and R 4 Independently selected from F, H, Cl or CH3.

[0053] In some embodiments, wherein A is CH2.

[0054] More preferably, wherein X is O.

[0055] In some embodiments, wherein A is O.

[0056] More preferably, wherein X is O.

[0057] More preferably, wherein R 2 It is i-Pr isopropyl, methyl or cyclopropyl.

[0058] In some embodiments, wherein A is O, X is NR 1 .

[0059] More preferably, wherein R 1 and R 2 Together with the X–C=C to which they are connected, they form a 6 Substituted 5-membered heterocyclic ring, that is:

[0060]

[0061] More preferably, wherein R 6 is H, methyl, ethyl, propyl, isopropyl or cyclopropyl.

[0062] A particularly preferred compound of formula (I) or (Ia), as described above, is

[0063]

[0064] Another particularly preferred compound of formula (I) or (Ia), as described above, is

[0065]

[0066] Another particularly preferred compound of formula (I) or (Ia), as described above, is

[0067]

[0068] Particularly preferred compounds of formula (I) or (Ia), as described above, are selected from one of the following structures:

[0069]

[0070] or a tautomer or a pharmaceutically acceptable salt thereof.

[0071] Particularly preferred compounds of formula (I) or (Ia), as described above, are selected from one of the following structures:

[0072]

[0073] or a tautomer or a pharmaceutically acceptable salt thereof.

[0074] In another aspect, provided herein is a compound of formula (II), or a tautomer or a pharmaceutically acceptable salt thereof,

[0075]

[0076] in:

[0077] R 1 It is OH, O-linked amino acid, OC(O)R 9 or OP(O)(OH)2, R 9 is H, alkoxy or lower alkyl;

[0078] R 2 is H or lower alkyl;

[0079] R 3 and R 4 Independently selected from H, F, Cl, Br or CH3.

[0080] Particularly preferred compounds of formula (II), as described above, are selected from one of the following structures:

[0081]

[0082] or a tautomer or a pharmaceutically acceptable salt thereof.

[0083] In another aspect, provided herein is a compound of formula (III), or a tautomer or a pharmaceutically acceptable salt thereof,

[0084]

[0085] in:

[0086] R 1 H, CH2OH, CH2O-linked amino acids, CH2OC(O)R 9 or CH2OP(O)(OH)2, R9 is H, alkoxy or lower alkyl;

[0087] R 2 is H or lower alkyl;

[0088] R 3 and R 4 Independently selected from H, F, Cl, Br or CH3.

[0089] Particularly preferred compounds of formula (III), as described above, are selected from one of the following structures:

[0090]

[0091] or a tautomer or a pharmaceutically acceptable salt thereof.

[0092] In another aspect, provided herein is a compound of formula (IV), or a tautomer or a pharmaceutically acceptable salt thereof,

[0093]

[0094] in:

[0095] R 1 H, CH2OH, CH2O-linked amino acids, CH2OC(O)R 9 or CH2OP(O)(OH)2, R 9 is H, alkoxy or lower alkyl;

[0096] R 2 is H or lower alkyl;

[0097] R 3 and R 4 Independently selected from H, F, Cl, Br or CH3.

[0098] Particularly preferred compounds of formula (IV), as described above, are:

[0099]

[0100] or a tautomer or a pharmaceutically acceptable salt thereof.

[0101] In another aspect, provided herein is a compound of formula (V), or a tautomer or a pharmaceutically acceptable salt thereof,

[0102]

[0103] in:

[0104] A is O, S, S(O)2, C(O) or CH2;

[0105] B is a substituted or unsubstituted 4-7 membered monocyclic ring or a 6-11 membered bicyclic ring having one or two heteroatoms in the ring, and the substituents are each independently and optionally selected from alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -OR 1 , -C(O)R 1 or-C(O)OR 1 One or more of;

[0106] R 1 Selected from hydrogen atoms, C 1-6 Alkyl or C 3-10 Cycloalkyl;

[0107] R 2 and R 3 Independently selected from H, F, Cl, Br or CH3.

[0108] A compound of formula (V), wherein A is O or CH2;

[0109] A compound of formula (V),

[0110] Wherein, B is selected from:

[0111]

[0112] R is selected from H, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or cycloalkyl,

[0113] R 5 Selected from H, C 1-6 Alkyl or C 3-10 Cycloalkyl,

[0114] R 6 is selected from H, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl or cycloalkyl.

[0115] More preferably, wherein R 4 is selected from H, CH2OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, cyclopropyl or cyclobutyl.

[0116] Particularly preferred compounds of formula (V), as described above, are selected from one of the following structures:

[0117]

[0118] It will be appreciated that the compounds of formula (I) or (Ia) or (II) to (V) of the present invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

[0119] As mentioned above, it has been found that the novel compounds of the present invention are thyroid hormone analogs. Therefore, the compounds of the present invention can be used to treat and / or prevent diseases regulated by thyroid hormone analogs, particularly metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, and can be used for other diseases, such as NASH (non-alcoholic steatohepatitis), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases. Obese patients are those with a body mass index of 25 or more.

[0120] Therefore, the present invention also relates to a pharmaceutical composition comprising a compound as defined above and a pharmaceutically acceptable carrier and / or adjuvant.

[0121] The present invention likewise includes the abovementioned compounds as active substances for use as therapy, in particular as active substances for the treatment and / or prevention of diseases which are modulated by thyroid hormone analogues, in particular metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia and diabetes and NASH (non-alcoholic steatohepatitis), atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and related conditions and diseases.

[0122] In another preferred embodiment, the present invention relates to a method for the treatment and / or prophylactic treatment of diseases modulated by thyroid hormone analogs, in particular metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, as well as NASH (non-alcoholic steatohepatitis), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases, the method comprising administering a compound as defined above to a human or animal. Preferably, the compound is administered in an amount of about 0.01 mg / kg to about 50 mg / kg per day, more preferably about 0.3 mg / kg to about 10 mg / kg per day, even more preferably about 0.70 mg / kg to about 3.5 mg / kg per day.

[0123] The invention also encompasses the use of the compounds as defined above for the therapeutic and / or prophylactic treatment of diseases which are modulated by thyroid hormone analogues, in particular metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, as well as NASH (non-alcoholic steatohepatitis), atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and related conditions and diseases.

[0124] The invention also relates to the use of the above compounds in the preparation of medicaments for the treatment and / or prophylactic treatment of diseases regulated by thyroid hormone analogs, in particular metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia and diabetes, as well as NASH (non-alcoholic steatohepatitis), atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases. Such medicaments include compounds as described above.

[0125] Prevention and / or treatment of metabolic diseases is a preferred indication. Diabetes, especially non-insulin dependent diabetes (type 2) is more preferred. Obesity is also more preferred. Hyperlipidemia is also more preferred, especially hypercholesterolemia.

[0126] The compounds of the present invention can be prepared from commercially available starting materials and using general synthetic techniques and procedures known to those skilled in the art. The following summarizes reaction schemes suitable for preparing such compounds. Further illustrations can be found in the specific embodiments described in detail below.

[0127] When B is C, A is CH2, X is O, R 2 is a lower alkyl group, R 3 and R 4 independently selected from F, H, Cl, CH3, R 5 yes Compounds of formula (I) or (Ia) are synthesized by Method A, a series of reactions in Scheme 1.

[0128] Method A

[0129]

[0130] R 2 is a lower alkyl group, R 3 and R 4 Independently selected from F, H, Cl, CH3; Z is Cl or Br; Pg 1 Select from commonly used protecting groups for phenolic hydroxyl groups.

[0131] Solution 1

[0132] When B is C, A is CH2, X is O, R 2 is a lower alkyl group, R 3 and R 4 independently selected from F, H, Cl, CH3, R 5 yes Compounds of formula (I) or (Ia) are synthesized by Method B, a series of reactions in Scheme 2.

[0133] Method B

[0134]

[0135] R 2 is a lower alkyl group, R 3 and R 4 are independently selected from F, H, Cl, CH3; Z is F, Cl or Br; Pg 1 and Pg 2 are independently selected from common protecting groups for phenolic hydroxyl groups.

[0136] Solution 2

[0137] When B is N, A is CH2, X is O, R 2 is a lower alkyl group, R 3 and R 4 are independently selected from F, H, Cl or CH3, R 5 yes Compounds of formula (I) or (Ia) are synthesized by Method C, a series of reactions in Scheme 3.

[0138] Method C

[0139]

[0140] R 2 is a lower alkyl group, R 3 and R 4 Independently selected from F, H, Cl, CH3.

[0141] Solution 3

[0142] When B is N, A is O, X is O, R 2 is a lower alkyl group, R 3 and R 4 independently selected from F, H, Cl, CH3, R 5 yes Compounds of formula (I) or (Ia) are synthesized by Method D, a series of reactions in Scheme 4.

[0143] Method D

[0144]

[0145] R 2 is a lower alkyl group, R 3 and R 4 Independently selected from F, H, Cl, CH3.

[0146] Solution 4

[0147] When B is N or C, A is O, and X is NR 1 , R 5 yes R 1 and R 2 , together with the X–C=C to which they are connected, form a 6 Substituted 5-membered heterocyclic ring, R 6 is selected from H, methyl, ethyl, propyl, isopropyl or cyclopropyl; R 3 and R 4 Compounds independently selected from F, H, Cl or CH3, (I) or (Ia) are synthesized by Method E, a series of reactions in Scheme 5.

[0148] Method E

[0149]

[0150] B is N or C, R 6 is selected from H, methyl, ethyl, propyl, isopropyl or cyclopropyl; R 3 and R 4 Independently selected from F, H, Cl, CH3.

[0151] Solution 5

[0152] definition

[0153] The compounds of the present invention include those compounds generally described above and are further illustrated by the classes, subclasses and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of the present invention, chemical elements are consistent with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, Ed: Smith, MB and March, J. John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0154] It should be understood that the purpose of the terms used herein is to describe specific embodiments, rather than being restrictive. In addition, any methods, devices and materials similar or equivalent to the description herein can be used in the practice or testing of the present invention, and preferred methods, devices and materials are now described.

[0155] As used herein, the term "alkyl" refers to, for example, branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g., alkenyl or alkynyl) hydrocarbon groups, which may be substituted or unsubstituted. When cyclic, the alkyl group is preferably C3 to C 12 , more preferably C4 to C 10 , more preferably C4 to C7. In the case of acyclic, the alkyl group is preferably C1 to C 10, more preferably C1 to C6, more preferably methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tert-butyl) or pentyl (including n-pentyl and isopentyl), more preferably methyl. It should be understood that the term "alkyl" used herein includes alkyl (branched or unbranched), substituted alkyl (branched or unbranched), alkenyl (branched or unbranched), substituted alkenyl (branched or unbranched), alkynyl (branched or unbranched), substituted alkynyl (branched or unbranched), cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloalkynyl and substituted cycloalkynyl.

[0156] As used herein, the term "lower alkyl" refers to, for example, branched or unbranched, cyclic or acyclic, saturated or unsaturated (e.g., alkenyl or alkynyl) hydrocarbon groups, wherein the cyclic lower alkyl is C5, C6 or C7, and wherein the acyclic lower alkyl is C1, C2, C3, C4, C5 or C6, preferably 1 to 4 carbon atoms. Typical lower alkyl groups include methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, isobutyl or tert-butyl), pentyl and hexyl. It should therefore be understood that the term "lower alkyl" used herein includes, for example, lower alkyl (branched or unbranched), lower alkenyl (branched or unbranched), lower alkynyl (branched or unbranched), cyclic lower alkyl, cyclic lower alkenyl and cyclic lower alkynyl. When attached to another functional group, the lower alkyl group used herein can be divalent, for example, -lower alkyl-COOH. Acyclic, branched or unbranched lower alkyl groups are preferred.

[0157] "Pharmaceutically acceptable", such as pharmaceutically acceptable carriers, excipients, etc., refers to pharmacologically acceptable and substantially non-toxic to the subject to whom the particular compound is administered. "Pharmaceutically acceptable salts" refer to conventional acid addition salts or base addition salts, which retain the biological effectiveness and properties of the compound of formula I and are formed by suitable organic or inorganic acids or organic or inorganic bases. Acid addition salt samples include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, phosphoric acid and nitric acid, and salts derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, etc. Base addition salt samples include salts derived from ammonium, potassium, sodium and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. Chemical modification of drug compounds (i.e., drugs) into salts is a well-known technique used to attempt to improve properties related to physical or chemical stability, such as the hygroscopicity, fluidity or solubility of the compound. See, for example, H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th ed. 1995) pp. 196 and 1456-1457. DETAILED DESCRIPTION OF THE INVENTION

[0159] Abbreviations: The present invention may use the following abbreviations

[0160]

[0161]

[0162]

[0163] The present invention can be better understood according to the following embodiments. However, it is easy for those skilled in the art to understand that the contents described in the embodiments are only used to illustrate the present invention and are not used to limit the present invention described in detail in the claims.

[0164] Unless otherwise indicated, the compounds of the present invention can be prepared from commercially available starting materials and using general synthetic techniques and procedures known to those skilled in the art. Chromatographic consumables and equipment can be purchased from companies such as AnaLogix, Inc, Burlington, WI; Analytical Sales and Services, Inc, Pompton Plains, NJ; Teledyne Isco, Lincoln, NE; VWR International, Bridgeport, NJ; and Rainin Instrument Company, Woburn, MA. Chemicals can be purchased from companies such as Aldrich, Argonaut Technologies, VWR, and Lancaster.

[0165] Material preparation

[0166] 1. Synthesis of 5-isopropyl-6-methoxypyridin-3-ol

[0167] 5-Isopropyl-6-methoxypyridin-3-ol was prepared according to Scheme 6 from the commercially available reagent 2-methoxypyridine.

[0168]

[0169] Solution 6

[0170] Step 1: Synthesis of 2-methoxy-3-(prop-1-en-2-yl)pyridine

[0171]

[0172] To a mixture of 2-methoxypyridine (20 g, 0.11 mmol, 1.0 eq), potassium propylene-2-trifluoroborate (23.61 g, 0.16 mmol, 1.5 eq) and K2CO3 (73.51 g, 0.53 mmol, 5.0 eq) in 200 mL DME and 40 mL water, Pd(dppf)Cl2-CH2Cl2 (8.68 g, 0.01 mmol, 0.1 eq) was added and the mixture was stirred at 90°C under nitrogen for 2 hours. After TLC showed the disappearance of the starting material, the mixture was cooled to room temperature and 100 mL of water was added. The mixture was extracted with 4X 100 mL EA, the organic layers were combined and concentrated. The residue was purified by flash chromatography (PE:EA=10:1) to give 12.5 g of the desired product as a brown oil, yield: 78.77%.

[0173] Step 2: Synthesis of 3-isopropyl-2-methoxypyridine

[0174]

[0175] To a solution of 2-methoxy-3-(prop-1-ene-2-yl)pyridine (12.5 g, 83.79 mmol, 1.0 eq) in 160 mL MeOH was added Pd / C (1.25 g, 10 w / w) and the mixture was stirred overnight at room temperature under hydrogen. After HPLC showed no starting material, the precipitate was filtered off and the filtrate was concentrated to give the desired product as a brown oil. Yield: 76.56%. 1 HNMR (400MHz, CDCl3-d3) δppm: 7.94-7.93 (m, 1H), 7.37 (d, J=7.2Hz, 1H), 6.78-6.73 (m, 1H), 3.88 (s, 3H), 3.15-3.07 (m, 1H), 1.14 (d, J=6.8Hz, 6H).

[0176] Step 3: Synthesis of 5-bromo-3-isopropyl-2-methoxypyridine

[0177]

[0178] 200mL MeCN 3-isopropyl-2-methoxypyridine (9.6g, 63.49mmol, 1.0eq), NBS (14.69g, 82.53mmol, 1.3eq) was added at room temperature, and the mixture was refluxed for 3 hours. After HPLC showed no starting material, MeCN was removed under vacuum and the residue was diluted with 100mL water, extracted with 4X 100mL EA, the organic layers were combined and concentrated, and the residue was purified by flash chromatography (PE: EA = 10: 1) to obtain 10.2g of the desired product as a brown oil, with a yield of 69.82%. 1 HNMR (400MHz, CDCl3-d3) δppm: 7.955 (d, J=1.6Hz, 1H), 7.433 (d, J=1.6Hz, 1H), 3.86 (s, 3H), 3.07-3.02 (m, 1H), 1.12 (d, J=6.8Hz, 6H).

[0179] Step 4: Synthesis of (5-isopropyl-6-methoxypyridin-3-yl)boronic acid

[0180]

[0181] At -70 ° C, to a solution of 5-bromo-3-isopropyl-2-methoxypyridine (5g, 21.73mmol, 1.0eq) in 30mL of anhydrous THF, n-BuLi (9.05mL, 21.73mmol, 2.4mol / L, 1.0eq) was added. When HPLC showed that no starting material was present, B(i-PrO)3 ​​(6.13g, 32.59mmol, 1.5eq) was added and stirred at -70 ° C for 1h, and then the reaction mixture was stirred at room temperature. Then 50mL of water was added and the pH value of the reaction mixture was adjusted to 3 with 2N HCl. After extraction with 3X 80mL of EA, the organic layers were combined and concentrated. The residue was purified by flash chromatography (DCM: MeOH = 10: 1) to give 1.05g of the desired product as a white solid, with a yield of 24.78%. LCMS: [M+1] = 389.2.

[0182] Step 5: Synthesis of 5-isopropyl-6-methoxypyridin-3-ol

[0183]

[0184] To a solution of (5-isopropyl-6-methoxypyridin-3-yl)boronic acid (4.1 g, 20 mmol, 1.0 eq) in 30 mL of THF was added H2O2 (11.9 g, 105 mmol, 5.0 eq) at 0°C. The reaction mixture was then stirred for 10 minutes, then AcOH (2.52 g, 42 mmol, 2.0 eq) was added dropwise, the mixture was heated to room temperature and stirred for a few minutes. 30 mL of an aqueous solution of a mixture of Na2S2O3 and NaHCO3 was then added to quench the reaction. The mixture was extracted with 4X 20 mL of EA. The organic layers were combined and concentrated. The residue was purified by reverse phase chromatography (water: MeOH = 1: 1) to give 1.1 g of the desired product as a brown oil, yield: 31.43%. LCMS: [M+1] = 168.1.

[0185] 2. Synthesis of 4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenol

[0186] -(4-Hydroxy-3-isopropylbenzyl)-3,5-dimethylphenol was prepared from the commercially available reagent 2-methoxypyridine according to Scheme 7

[0187]

[0188] Solution 7

[0189] Step 1: Synthesis of compound 2

[0190]

[0191] Under a nitrogen atmosphere, at 0°C, tert-butyldimethylsilyl chloride (24.1 g, 159.8 mmol, 1.2 eq) was added in batches to a solution of compound 1 (20 g, 133.2 mmol, 1.0 eq) and imidazole (18.1 g, 266.4 mmol, 2.0 eq) in 200 mL of DMF, and the mixture was stirred at room temperature for 30 min. The mixture was cooled to 0°C, and water was then added. The mixture was extracted with dichloromethane, and the organic phase was washed with water and brine, and then dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by chromatography using heptane / ethyl acetate (100:1) as the mobile phase. The solvent was removed under reduced pressure to give compound 2 (23 g, light red liquid, yield 65%). LCMS: (ESI-MS): [M+H] + =265.2; 1 HNMR (400MHz, CDCl3) δppm: 10.50 (s, 1H), 6.55 (s, 2H), 2.59 (s, 6H), 0.98 (s, 9H), 0.26 (s, 6H).

[0192] Step 2: Synthesis of compound 4

[0193]

[0194] To a solution of compound 3 (20 g, 146.8 mmol, 1.0 eq) in MeCN (200 mL) was added NBS (28.8 g, 161.6 mmol, 1.1 eq) at 0°C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered, and the filter cake was washed with hexane and dried to give a crude product, compound 4 (25 g), which was used directly in the next step without further purification. LCMS: (ESI-MS): [M+H] + =215.0,217.0.

[0195] Step 3: Synthesis of compound 5

[0196]

[0197] Under an argon atmosphere, sodium hydride (60%, 7g, 174.4mmol, 1.5eq) was added to anhydrous THF (200mL) in batches at 0°C, and then a solution of compound 4 (25g, 116.2mmol, 1.0eq) in THF (100mL) was added dropwise. After addition, the reaction mixture was heated to room temperature and stirred for 30 minutes. MOMCl (18.7g, 232.4mmol, 2.0eq) was then added dropwise at 0°C. The mixture was heated to room temperature and stirred for 15 minutes, then diluted with water at 0°C. The aqueous layer was extracted 3 times with hexane, dried with sodium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 100). The desired colorless, transparent oily compound 5 (20g, 66%) was obtained.

[0198] Step 4: Synthesis of compound 6

[0199]

[0200] Under argon atmosphere, n-BuLi (2.4M, 20.8ml, 50mmol, 1.2eq) was added dropwise to a solution of compound 5 (13g, 50mmol, 1.2eq) in THF (120mL) at -78°C. The solution was stirred at -78°C for 30 minutes. A solution of compound 2 (11.1g, 42mmol, 1.0eq) in THF (30mL) was added dropwise to the above mixture within 30 minutes. After stirring for 1h, the reaction was quenched with a saturated aqueous solution of ammonium chloride (100ml). After stratification, the aqueous phase was extracted with ethyl acetate (200mL). The combined organic layer was washed with brine (200mL) and dried over MgSO4. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1:100). The desired colorless and transparent oily compound 6 (11.1g, colorless liquid, yield 50%) was obtained. 1 HNMR (400MHz, CDCl3) δppm: 7.00 (s, 1H), 6.75-6.70 (m, 2H), 6.31 (s, 2H), 6.02 (s, 1H), 4.96 (s, 2H), 3.27(s, 3H), 3.11-3.09(m, 1H), 2.00(s, 6H), 0.99-0.95(m, 6H), 0.78(s, 9H), 0.00(s, 6H).

[0201] Step 5: Synthesis of compound 7

[0202]

[0203] To a solution of compound 6 (11.1 g, 24.9 mmol, 1.0 eq) in EtOH / AcOH=100 (15 mL) was added 10% Pd / C (6 g), followed by treatment with hydrogen. The reaction mixture was stirred at 50° C. for 5 h, the reaction mixture was filtered, and the filtrate was concentrated to give a crude product, compound 7 (7.5 g, colorless oil, 67% yield), which was used directly in the next step without further purification. 1 HNMR (400MHz, CDCl3) δppm: 6.93-6.88 (m, 2H), 6.68-6.66 (m, 1H), 6.56 (s, 2H), 5.15 (s, 2H), 3.91 ( s, 2H), 3.48 (s, 3H), 3.30-3.27 (m, 1H), 2.18 (s, 6H), 1.18-1.16 (m, 6H), 1.00 (s, 9H), 0.21 (s, 6H).

[0204] Step 6: Synthesis of compound 8

[0205]

[0206] To a stirred solution of compound 7 (7.5 g, 17.5 mmol, 1.0 eq) in THF (100 mL) was added TBAF (6.9 g, 26.2 mmol, 1.5 eq) at 0°C. The reaction mixture was stirred at room temperature for 20 min, diluted with EA and washed with water (100 mL x 2) and brine (100 mL x 2). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with EA / PE (1:4) to give oily compound 8 (7.5 g, yield 75%). LCMS: (ESI-MS): [MH] + =313.2. 1 HNMR (400MHz, CDCl3) δppm: 6.83 (s, 1H), 6.79-6.77 (m, 1H), 6.55-6.53 (m, 1H), 6.44 (s, 1H), 5. 06-5.01 (m, 2H), 3.79 (s, 2H), 3.37 (s, 3H), 3.20-3.16 (m, 1H), 2.08 (s, 6H), 1.10-1.06 (m, 6H).

[0207] Example 1

[0208] 2-(4-(4-Hydroxymethoxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-(methylsulfonyl)acetamide (I1)

[0209] Step 1: Synthesis of compound 9

[0210]

[0211] At 0°C, ethyl bromide (368 mg, 2.2 mmol, 1.1 eq) was added to a solution of compound 8 (630 mg, 2 mmol, 1.0 eq) and K2CO3 (552 mg, 4 mmol, 2.0 eq) in DMF (7 mL), and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was concentrated, then diluted with water (10 mL), and extracted with EA (10 mL×3). The combined organic layer was washed with brine (20 mL), dried, concentrated, and purified by n-hexane / EA (3:1) silica gel column to give compound 9 (700 mg, oily liquid, yield 87%). 1HNMR (300MHz, CDCl3) δppm: 6.93-6.87 (m, 2H), 6.64-6.62 (m, 3H), 5.14 (s, 2H), 4.60 (s, 2H), 4.29-4.25 ( m, 2H), 3.90 (s, 2H), 3.47 (s, 3H), 3.30-3.26 (m, 1H), 2.21 (s, 6H), 1.33-1.28 (m, 3H), 1.21-1.16 (m, 6H).

[0212] Step 2: Synthesis of compound 10

[0213]

[0214] To a solution of compound 9 (700 mg, 1.75 mmol, 1.0 eq) in MeOH / THF / H2O=1:1:1 (12 mL) was added NaOH (210 mg, 5.25 mmol, 3.0 eq) at room temperature. The mixture was stirred at room temperature for 4 h. After the reaction was completed, the reaction was acidified with 2N HCl and a precipitate was formed when the solution was cooled to room temperature. The reaction was then diluted with water and extracted with EA (15 mL×2). The combined organic layers were treated with brine, dried and concentrated to give the desired product compound 10 (500 mg, white solid, yield 77%). LCMS: (ESI-MS): [M+Na] + =395.1; 1 HNMR (300MHz, DMSO-d6) δppm: 6.96 (s, 1H), 6.89-6.86 (m, 1H), 6.60 (s, 3H), 5.14 (s, 2H), 4 .51 (s, 2H), 3.84 (s, 2H), 3.37 (s, 3H), 3.24-3.20 (m, 1H), 2.15 (s, 6H), 1.16-1.12 (m, 6H).

[0215] Step 3: Synthesis of compound 11

[0216]

[0217] At 0°C, EDCI (384 mg, 2.0 mmol, 1.5 eq), methylsulfonamide (140 mg, 1.47 mmol, 1.1 eq) and DMAP (244 mg, 2 mmol, 1.5 eq) were added to a solution of compound 10 (500 mg, 1.34 mmol, 1.0 eq) in 20 mL of DCM, and the resulting solution was stirred for another 4 h at room temperature. After the reaction was completed, it was diluted with 10% aqueous citric acid solution (20 mL), extracted with DCM (20 mL×2), and the combined organic layers were washed with brine (20 mL), dried, and concentrated to give compound 11 (390 mg, oily liquid, yield 65%). LCMS: (ESI-MS): [M+Na] + =472.1; 1 HNMR (300MHz, CDCl3) δppm: 6.85-6.81 (m, 2H), 6.56-6.54 (m, 2H), 5.08 (s, 2H), 4.51 (s, 2H) , 3.85(s, 2H), 3.40(s, 3H), 3.28(s, 2H), 3.24-3.20(m, 1H), 2.16(s, 6H), 1.15-1.10(m, 6H).

[0218] Step 4: Synthesis of compound I1:

[0219]

[0220] To a solution of compound 11 (390 mg, 0.87 mmol, 1.0 eq) in methanol (20 ml) was added 20 ml of 6N HCl. The reaction mixture was stirred at room temperature overnight, diluted with water (10 ml), and extracted with ethyl acetate (2×20 ml). The combined organic extracts were washed with brine (20 ml), dried over MgSO4, concentrated and purified by pre-HPLC to give compound I1 (80 mg, white solid, yield 23%). LCMS: (ESI-MS): [MH] + =404.0; 1 HNMR (400MHz, DMSO-d6) δppm: 11.97 (s, 1H), 8.97 (s, 1H), 6.85 (s, 1H), 6.62-6.60 (m, 3H), 6.47-6.4 5 (m, 1H), 4.64 (s, 2H), 3.80 (s, 2H), 3.28 (s, 3H), 3.15-3.11 (m, 1H), 2.17 (s, 6H), 1.11-1.10 (m, 6H).

[0221] Example 2

[0222] 5-((4-(4-Hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)methyl)isoxazol-3-ol (I2)

[0223] Step 1: Synthesis of compound 14

[0224]

[0225] To a solution of compound 12 (3.8 g, 49.3 mmol, 1.0 eq) and DBU (9 g, 59.1 mmol, 1.2 eq) in MeOH (75 mL) was added compound 13 (7 g, 49.3 mmol, 1.0 eq) at 0°C, and the mixture was stirred at 0°C for 30 min. The reaction mixture was then stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EA (100 mL×3). The combined organic layers were washed with brine (100 mL), dried, concentrated and purified by heptane / EA (3:1) silica gel column to give compound 14 (3 g, white solid, yield 42%). LCMS: (ESI-MS): [M+H] + =144.1; 1 HNMR (400MHz, DMSO-d6) δppm: 11.92 (s, 1H), 6.76 (s, 1H), 3.87 (s, 3H).

[0226] Step 2: Synthesis of compound 15

[0227]

[0228] At 0°, TEA (2.91 ml, 14 mmol, 2.0 eq) and MOMCl (0.69 ml, 14 mmol, 2.0 eq) were added to a solution of compound 14 (1 g, 6.99 mmol, 1.0 eq) in 25 mL THF, and the resulting solution was stirred for another 2 hours at room temperature. The reaction mixture was diluted with water (30 mL), extracted with EA (50 mL×2), and the combined organic layer was washed with brine (50 mL), dried, concentrated, and purified with a heptane / EA (10:1) silica gel column to give compound 15 (1 g, oily liquid, yield 76%). LCMS: (ESI-MS): [M+H] + =188.1; 1 HNMR (300MHz, CDCl3) δppm: 6.57 (s, 1H), 5.29 (s, 2H), 3.87 (s, 3H), 3.49 (s, 3H).

[0229] Step 3 Synthesis of compound 16

[0230]

[0231] At 0°C, LiAlH4 (305 mg, 8.01 mmol, 1.5 eq) was slowly added to a solution of compound 15 (1.0 g, 5.34 mmol, 1.0 eq) in THF (15 mL), and the resulting solution was stirred for another 1 h at room temperature. The reaction mixture was carefully quenched with water (40 mL), extracted with EA (30 mL×2), and the combined organic layers were washed with brine (50 mL), dried, concentrated and purified by heptane / EA (5:1) silica gel column to give compound 16 (380 mg, oily liquid, yield 45%). LCMS: (ESI-MS): [M+H] + =160.1; 1 HNMR (300MHz, CDCl3) δppm: 5.97 (s, 1H), 5.29 (s, 2H), 4.65 (s, 2H), 3.53 (s, 3H).

[0232] Step 4: Synthesis of compound 17

[0233]

[0234] To a solution of compound 16 (380 mg, 2.4 mmol, 1.0 eq) and PPh3 (940 mg, 3.6 mmol, 1.5 eq) in 10 mL of DCM was added CBr4 (1.2 g, 3.6 mmol, 1.5 eq) at 0°C, and the reaction mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was concentrated and purified by heptane / EA (3:1) silica gel column to give compound 17 (120 mg crude product). LCMS: (ESI-MS): [M+H] + =222.0,224.0; 1 HNMR (400MHz, CDCl3) δppm: 5.76 (s, 1H), 5.11 (s, 2H), 4.13 (s, 2H), 3.36 (s, 3H).

[0235] Step 5: Synthesis of compound 18

[0236]

[0237] To a solution of compound 17 (120 mg, 0.54 mmol, 1.5 eq) and compound 8 (114 mg, 0.36 mmol, 1.0 eq) in toluene (3 mL) were added K2CO3 (110 mg, 0.79 mmol, 2.2 eq) and TBAI (8 mg, 0.02 mmol, 0.06 eq). The reaction mixture was then stirred at room temperature for 12 h. The reaction mixture was diluted with water (10 mL) and extracted with EA (10 mL×2). The combined organic layer was washed with brine (15 mL), dried, concentrated and purified with hexane / EA (1:1) silica gel column to give compound 18 (80 mg, oily liquid, yield 32%). LCMS: (ESI-MS): [M+H] + =456.2; 1 HNMR (400MHz, CDCl3) δppm: 6.86-6.81 (m, 2H), 6.58-6.52 (m, 3H), 5.77 (s, 1H), 5.12-5.08 (m, 4H), 4.85 ( s, 2H), 3.85 (s, 2H), 3.42-3.35 (m, 6H), 3.23-3.20 (m, 1H), 2.15 (s, 6H), 1.52 (s, 6H), 1.12-1.10 (m, 6H).

[0238] Step 6: Synthesis of Compound I2

[0239]

[0240] 6N HCl (2 mL) was added to a solution of compound 18 (80 mg, 0.17 mmol, 1.0 eq) in methanol (2 mL). The reaction mixture was stirred at room temperature overnight, diluted with water (2 mL), and extracted with ethyl acetate (2×5 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4, concentrated and purified by pre-HPLC to give compound I2 (24 mg, white solid, 40% yield). LCMS: (ESI-MS): [M+H] + =368.2; 1 HNMR (400MHz, DMSO-d6) δppm: 11.31 (s, 1H), 8.97 (s, 1H), 6.84 (s, 1H), 6.72 (s, 1H), 6.61 (d, J=8.0Hz, 1H), 6.4 5 (d, J=8.4Hz, 1H), 6.12 (s, 1H), 5.07 (s, 2H), 3.80 (s, 2H), 3.14-3.11 (m, 1H), 2.16 (s, 6H), 1.10-1.09 (m, 6H).

[0241] Example 3

[0242] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I3)

[0243] Step 1: Synthesis of 4-bromo-3,5-dichloroaniline (20):

[0244]

[0245] At 0°C, a solution of N-bromosuccinimide (14 g, 247 mmol) in MeCN (100 mL) was added dropwise to a solution of 3,5-dichloroaniline (40 g, 247 mmol) in MeCN (300 mL). The mixture was then warmed to room temperature and stirred for 3 hours. After the reaction was complete, an aqueous solution of NaHCO3 (100 mL) was added and stirred for 15 min, then concentrated. The residue was extracted with EA (3X100 mL), and the organic layers were combined and concentrated. The residue was purified by a PE silica gel column to give the desired product compound 20 (45 g, white solid, 76% yield). LCMS: (ESI-MS): [M+H] + =239.9.

[0246] Step 2: Synthesis of compound 21

[0247]

[0248] LiHMDS (55mL, 134mmol, 2.4M) was added dropwise to a solution of 4-bromo-3,5-dichloroaniline (29g, 87mmol) in THF (300mL) at -78°C and stirred for 0.5h. Then BnBr (30g, 175mmol) was added dropwise to the above solution. The mixture was heated to room temperature and stirred for 2h. After the reaction was completed, NH4Cl (100mL) aqueous solution was added and stirred for 15min. Then EA (3X100mL) was extracted, the organic layers were combined and concentrated. The residue was purified by PE / EA=30 / 1 silica gel column to obtain the desired product 21 (25.7g, white solid, yield 51%). 1 HNMR (400MHz, DMSO-d6) δppm 10.13 (s, 1H), 7.38 (t, J=7.3Hz, 4H), 7.28 (dd, J=15.0, 7.3Hz, 6H), 6.79 (s, 2H), 4.88 (s, 4H). LCMS: (ESI-MS): [M+H] + =420.0.

[0249] Step 3: Synthesis of compound 22

[0250]

[0251] To a solution of 21 (20 g, 47 mmol, 1.0 eq) in anhydrous THF (200 mL) was added n-BuLi (30 mL, 70 mmol, 2.4 mol / L, 1.5 eq) at -78 °C and stirred for 0.5 h. Then, a solution of N-formylmorpholine (10.9 g, 95 mmol, 2.0 eq) in THF (30 mL) was added at -78 °C and stirred for 1 h. The mixture was then warmed to room temperature and stirred overnight. After the reaction was complete, 100 mL of water was added. The mixture was extracted with EA (3 × 100 mL), and the organic layers were combined and concentrated. The residue was purified by flash chromatography (PE: EA = 10: 1) to give the desired product 22 (10.2 g, white solid, 51% yield). 1 HNMR (400MHz, CDCl3) δppm 10.25 (s, 1H), 7.27 (dq, J=14.3, 7.1Hz, 6H), 7.11 (d, J=7.2Hz, 4H), 6.62 (s, 2H), 4.60 (s, 4H).

[0252] Step 4: Synthesis of compound 23

[0253]

[0254] At -78 ° C, to a solution of 5-bromo-3-isopropyl-2-methoxypyridine (6.2 g, 25 mmol, 1.0 eq) in anhydrous THF (95 mL), n-BuLi (12.8 mL, 30 mmol, 2.4 mol / L, 1.2 eq) was added and stirred for 0.5 h. Then a solution of compound 22 (9.5 g, 25 mmol, 1.0 eq) in THF (20 mL) was added and stirred for 1 h at -78 ° C. The mixture was then heated to room temperature and stirred overnight. After the reaction was complete, 100 mL of water was added and extracted with EA (3 × 100 mL), the organic layers were combined and concentrated, and the residue was purified by flash chromatography (PE / EA=5 / 1) to obtain the desired product 23 (5 g, white solid, 35% yield). 1HNMR (400MHz, CDCl3) δppm7.63 (d, J=1.3Hz, 1H), 7.52 (d, J=1.9Hz, 1H), 7.29 (t, J=7.3Hz, 4H), 7.22 (t, J=7.2Hz, 2H), 7.12 (d, J=7.3Hz, 4H), 6.61 (s, 2H), 6.34 (d, J=10.5Hz, 1H), 4.54 (s, 4H), 3.86 (s, 3H), 3.10–3.02 (m, 1H), 1.13 (dd, J=6.8, 4.3Hz, 6H). LCMS: (ESI-MS): [M+H] + =523.1.

[0255] Step 5 Synthesis of Compound 24

[0256]

[0257] At 0 ° C, TFA (1.1 g, 9.6 mmol, 5 eq) and triethylsilane (1.1 g, 9.6 mmol, 5 eq) were added to a solution of compound 23 (1 g, 1.92 mmol, 1.0 eq) in anhydrous THF (10 mL) and stirred for 0.5 h. The mixture was then heated to room temperature and stirred overnight. After the reaction was complete, the reaction mixture was concentrated. The resulting residue was extracted with EA (3X50 mL), and the organic layers were combined and concentrated. The residue was purified by PE / EA=1 / 5 silica gel column to obtain the desired product 24 (720 mg, white solid, 74% yield). 1 HNMR (300MHz, CDCl3) δppm7.83 (s, 1H), 7.41-7.27 (m, 7H), 7.19 (d, J=6.9Hz, 4H), 6.70 (s, 2H), 4.59 (s, 4H), 4.12 (s, 2H), 3.92 (s, 3H), 3.14-3.09 (m, 1H), 1.19 (d, J=6.9, 6H). LCMS: (ESI-MS): [M+H] + =507.1.

[0258] Step 6: Synthesis of compound 25

[0259]

[0260] Pd / C (0.2 g, 20% w / w) was added to a solution of compound 24 (1.0 g, 1.98 mmol, 1 eq) in 10 mL of EtOAc and the mixture was stirred at room temperature under hydrogen. After HPLC showed the disappearance of the starting material, the solid was filtered off and the filtrate was concentrated, and the residue was purified by PE / EA=1 / 1 silica gel column to give the desired product 25 (350 mg, white solid, yield: 54.3%). 1 HNMR (300MHz, CDCl3) δppm 8.11 (s, 1H), 7.38 (s, 1H), 6.65 (s, 2H), 4.07 (s, 2H), 3.78 (s, 3H), 3.15-3.06 (m, 1H), 1.24 (d, J=9.3, 6H). LCMS: (ESI-MS): [M+H] + =327.0.

[0261] Step 7: Synthesis of compound 26

[0262]

[0263] At 0 ° C, NaNO was added dropwise to a solution of compound 25 (350 mg, 1.07 mmol, 1.0 eq) in 4N HCl (5 mL) (104 mg, 1.5 mmol, 1.4 eq) in 1.0 mL water. The mixture was stirred for 30 min and a mixture of (2-cyanoacetyl)ethyl carbamate (210 mg, 1.34 mmol, 1.125 eq) and NaOAc (298 mg, 3.63 mmol, 3.375 eq) in 3 mL EtOH was added. After stirring for 40 minutes, EtOH was removed under vacuum, 10 mL water and 20 mL DCM were added, and the organic layer was concentrated to obtain the desired product (190 mg, yellow solid, yield: 35.8%). 1 HNMR (400MHz, CDCl3) δppm13.80 (s, 1H), 8.58 (s, 1H), 7.75 (s, 1H), 7.29 (d, J=1.5Hz, 1H), 7.19 (s, 1H), 4.19 (dd, J=14.3, 7. 2Hz, 2H), 4.09 (d, J=11.7Hz, 2H), 3.84 (d, J=2.2Hz, 3H), 3.02 (dd, J=13.7, 6.9Hz, 1H), 1.28–1.16 (m, 3H), 1.16–1.02 (m, 6H). LCMS: (ESI-MS): [M+H] + =492.1.

[0264] Step 8: Synthesis of compound 27

[0265]

[0266] To a solution of compound 26 (190 mg, 0.386 mmol, 1.0 eq) in 2 mL of AcOH was added AcONa (158 mg, 1.93 mmol, 5.0 eq) and the mixture was heated to 120° C. After 1.5 h, the mixture was cooled to 0° C. and diluted with 10 mL of water. The precipitate was collected by filtration to give the desired product 27 (160 mg, white solid, 92.9% yield). 1 HNMR (400MHz, DMSO-d6) δppm7.77 (d, J=3.2Hz, 1H), 7.70 (s, 2H), 7.47 (d, J=2.2Hz, 1H), 4.24 (s, 2H), 3.84 (s, 4H), 3.06 (dp, J=13.7, 6.6Hz, 1H), 1.14 (d, J=6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =446.3.

[0267] Step 9: Synthesis of Compound I3

[0268]

[0269] To a solution of 27 (160 mg, 0.36 mmol, 1.0 eq) in 2 mL of dioxane, HBr (319 mg, 1.79 mmol, 5.0 eq, 48% aq) was added, heated to 60 ° C and stirred for 3 h. When HPLC showed no starting material, 10 mL of water was added and the mixture was extracted with 3X 10 mL of DCM. The organic layers were combined and concentrated. The residue was purified by Prep-HPLC (60% ACN aqueous solution-0.1% TFA as additive) to obtain the desired product I3 (44 mg, white solid, yield: 28.4%). 1 HNMR (400MHz, MeOD): δ ppm 7.72 (s, 2H), 7.44 (d, J = 2.4Hz, 1H), 6.96 (d, J = 2.3Hz, 1H), 4.17 (s, 3H), 3.16–3.02 (m, 1H), 1.16 (d, J = 6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =432.1.

[0270] Example 4

[0271] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I4)

[0272] Step 1: Synthesis of compound 29

[0273]

[0274] To a solution of 5-isopropyl-6-methoxypyridine-3-ol (1.0 g, 5.98 mmol, 1.0 eq) and 28 (1.35 g, 5.98 mmol, 1.0 eq) in 20 mL THF was added t-BuOK (1.34 g, 11.96 mmol, 2.0 eq). The mixture was stirred overnight at 50 ° C under nitrogen, and when HPLC showed no starting material, 50 mL of water was added and extracted with 3X 50 mL of EA. The organic layers were combined and concentrated. The residue was purified by methanol slurrying to give 1.5 g of the desired product 29 as a yellow solid, yield: 70%. 1 HNMR (300MHz, CDCl3-d3) δppm: (s, 2H), 7.46 (d, J=2.4Hz, 1H), 7.17 (d, J=2.4Hz, 1H), 3.94 (s, 3H), 3.20-3.15 (m, 1H), 1.12 (d, J=6.8Hz, 6H).

[0275] Step 2: Synthesis of compound 30

[0276]

[0277] To a solution of 29 (1.5 g, 4.2 mmol, 1 eq) in 15 mL of MeOH was added Pd / C (0.3 g, 20% w / w) and the mixture was stirred at room temperature under hydrogen. After HPLC showed the disappearance of the starting material, the solid was filtered off and the filtrate was concentrated, and the residue was purified by flash chromatography (PE:EA=1:1) to give 500 mg of the desired product 30 as a white solid, yield: 36.3%.

[0278] Step 3: Synthesis of compound 31

[0279]

[0280] At 0 ° C, to 30 (480 mg, 1.47 mmol, 1.0 eq) in concentrated HCl (0.84 mL) and water (2.16 mL) solution was added dropwise NaNO2 (141.45 mg, 2.02 mmol, 1.4 eq) in 1.08 mL water solution, the mixture was stirred for 30 min, and (2-cyanoacetyl) ethyl carbamate (257.63 mg, 1.65 mmol, 1.125 eq) and NaOAc (405.99 mg, 4.95 mmol, 3.375 eq) in 7.2 mL EtOH mixture was added. After stirring for 40 minutes, EtOH was removed under vacuum, 10 mL of water and 40 mL of DCM were added, and the organic layer was concentrated to give 600 mg of crude product 31, which was used in the next step without purification. 1 HNMR (400MHz, CDCl3-d3) δppm: (s, 1H), 8.42 (s, 1H), 7.38-7.33 (m, 1H), 7.14 (s, 2H), 7.08 (s, 1H) ), 4.28 (q, J=6.8Hz, 2H), 3.85 (s, 3H), 3.08 (s, 1H), 1.29 (t, J=6.8Hz, 3H), 1.12 (d, J=6.8Hz, 6H).

[0281] Step 4: Synthesis of compound 32

[0282]

[0283] To a solution of 31 (600 mg, 1.2 mmol, 1.0 eq) in 12 mL of AcOH was added AcONa (497.76 mg, 6.07 mmol, 5.0 eq) and the mixture was heated to 120°C. After 1.5 h, the mixture was cooled to 0°C and diluted with 36 mL of water. The precipitate was collected by filtration to give 430 mg of the desired product 32 as a white solid, two-step yield from product 30: 65.3%. LCMS: [M-1] = 448.0. 1 HNMR (400MHz, CDCl3-d3) δppm: 7.58 (s, 2H), 7.39 (s, 1H), 7.20 (s, 1H), 3.90 (s, 3H), 3.10-3.07 (m, 1H), 1.13 (d, J = 6.8Hz, 6H).

[0284] Step 5: Synthesis of Compound I4

[0285]

[0286] To a solution of 32 (170 mg, 0.38 mmol, 1.0 eq) in 6 mL of dioxane was added HBr (319 mg, 1.89 mmol, 5.0 eq, 60% aq) and heated to 60 ° C and stirred for 3 hours. When HPLC showed no starting material, 10 mL of water was added and extracted with 3X 10 mL of DCM. The organic layers were combined and concentrated. The residue was purified by Prep-HPLC (0.1% TFA and MeCN as eluents) to give 62 mg of the desired product I4 as a white solid, yield: 37.6%. LCMS: [M-1] = 434.0. 1 HNMR (300MHz, DMSO-d6) δppm: (br, 1H), 7.78 (s, 2H), 7.71 (s, 1H), 7.27 (d, J=3Hz, 1H), 6.70 (d, J=3Hz, 1H), 3.02-2.97 (m, 1H), 1.13 (d, J=6.9Hz, 6H).

[0287] Example 5

[0288] 2-(3-Chloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I5)

[0289] Step 1: Synthesis of compound 33

[0290]

[0291] At room temperature, t-BuOK (1.33 g, 11.90 mmol, 2.0 eq) was added to a solution of 5-isopropyl-6-methoxypyridine-3-ol (1.0 g, 5.95 mmol, 1.0 eq) and 2-chloro-1-fluoro-4-nitrobenzene (1.05 g, 5.95 mmol, 1.0 eq) in 20 mL of THF. The mixture was stirred overnight at 50 ° C. When HPLC showed that there was no starting material, the mixture was cooled to room temperature, 50 mL of water was added and extracted with 3x 50 mL of EtOAc. The organic layers were combined and concentrated. The residue was purified by PE / EA=100 / 1 silica gel column to obtain the desired product 33 (890 mg, yellow solid, yield: 47%). 1HNMR (400MHz, CDCl3) δppm8.31 (d, J=2.7Hz, 1H), 7.98 (dd, J=9.1, 2.7Hz, 1H), 7.77 (d, J=2.8Hz, 1H), 7.17 (d, J=2.7Hz, 1H), 6.73 (d, J=9.1Hz, 1H), 3.92 (s, 3H), 3.14-3.11 (m, 1H), 1.14 (d, J=6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =322.8.

[0292] Step 2: Synthesis of compound 34

[0293]

[0294] To a solution of 33 (890 mg, 2.81 mmol, 1 eq) in EtOAc (10 mL) was added Pd / C (0.2 g, 20% w / w) and the mixture was stirred at room temperature under hydrogen. After HPLC showed the disappearance of the starting material, the solid was removed by filtration and the filtrate was concentrated to give the desired product 34 (745 mg, black oil, yield: 86%). 1 HNMR (400MHz, CDCl3) δppm7.53 (d, J=2.9Hz, 1H), 7.08 (d, J=2.8Hz, 1H), 6.74-6.64 (m, 2H), 6 .46 (dd, J=8.7, 2.7Hz, 1H), 3.84 (d, J=6.0Hz, 3H), 3.11-3.01 (m, 1H), 1.11 (d, J=6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =292.9.

[0295] Step 3: Synthesis of compound 35

[0296]

[0297] To a solution of 34 (745 mg, 2.55 mmol, 1.0 eq) in 4N HCl (10 mL) was added a solution of NaNO2 (246.5 mg, 3.57 mmol, 1.4 eq) in 2.0 mL of water at 0°C. The mixture was stirred for 30 min, and a mixture of ethyl (2-cyanoacetyl)carbamate (448.5 mg, 2.87 mmol, 1.125 eq) in 5 mL of pyridine was added. After stirring for 40 minutes, 10 mL of water and 20 mL of EtOAc were added, and the organic layer was dried and concentrated to give the desired product 35 (780 mg, crude), which was used directly in the next step. LCMS: (ESI-MS): [M+H] +=459.8.

[0298] Step 4: Synthesis of compound 36

[0299]

[0300] To a solution of 35 (780 mg, 1.7 mmol, 1.0 eq) in 10 mL of AcOH was added AcONa (697 mg, 8.49 mmol, 5.0 eq) and the mixture was heated to 120°C. After 1.5 h, the mixture was cooled to 0°C and diluted with 10 mL of water, and the precipitate was collected by filtration to give the desired product 36 (530 mg, crude), which was used directly in the next step without purification. LCMS: (ESI-MS): [M+H] + =413.8.

[0301] Step 5: Synthesis of Compound I5

[0302]

[0303] To 36 (530mg, 1.28mmol, 1.0eq) in 8mL dioxane solution, add HBr (2ml, 48%aq) and be heated to 60 ℃ and stir 3 hours.When HPLC shows no starting material, 10mL water is added to the mixture, and the mixture is extracted with 3x10mLEA. Combine organic layers and concentrate. Residue is purified by Prep-HPLC (40%ACN aqueous solution-0.1%TFA as additive) to obtain the desired product I5 (23.8mg, red solid, 3 step yield: 2.3%). 1 HNMR (400MHz, MeOD4) δppm7.74 (d, J=2.5Hz, 1H), 7.47 (dd, J=8.9, 2.5Hz, 1H), 7.35 (d, J=2.9Hz, 1H) , 7.20 (d, J=3.0Hz, 1H), 7.07 (d, J=8.9Hz, 1H), 3.15 (dt, J=13.7, 6.8Hz, 1H), 1.20 (t, J=8.2Hz, 6H). LCMS: (ESI-MS): [M+H] + =399.8.

[0304] Example 6

[0305] 2-(4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)-3,5-dimethylphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I6)

[0306] Step 1 Synthesis of compound 37

[0307]

[0308] To a mixture of 5-isopropyl-6-methoxypyridine-3-ol (1.0 g, 5.98 mmol, 1.0 eq) and 2-fluoro-1,3-dimethyl-5-nitrobenzene (1.0 g, 5.98 mmol, 1.0 eq) in 20 mL of THF was added t-BuOK (1.33 g, 11.90 mmol, 2.0 eq). The mixture was stirred overnight at 50 ° C under nitrogen. When HPLC showed no starting material, water (50 mL) was added to the mixture and the mixture was extracted with EtOAc (3x50 mL). The organic layers were combined and concentrated. The residue was purified by silica gel column (PE / EA=100 / 1) to give the desired product 37 (670 mg, yield: 36%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δppm7.94 (s, 2H), 7.25 (d, J=2.9Hz, 1H), 7.01 (d, J=2.9Hz, 1H), 3.8 7 (d, J=4.2Hz, 3H), 3.18–2.97 (m, 1H), 2.16 (d, J=4.0Hz, 6H), 1.13 (dd, J=6.8, 4.2Hz, 6H). LCMS: (ESI-MS): [M+H] + =316.9.

[0309] Step 2 Synthesis of compound 38

[0310]

[0311] To a solution of 37 (890 mg, 2.81 mmol, 1 eq) in EtOAc (10 mL) was added Pd / C (0.2 g, 20% w / w) and the mixture was stirred at room temperature under hydrogen. After HPLC showed the disappearance of the starting material, the solid was removed by filtration and the filtrate was concentrated to give the desired product 38 (560 mg, yield: 69.5%) as a white solid. 1 HNMR (400MHz, CDCl3) δppm7.31 (d, J=2.9Hz, 1H), 6.95 (d, J=2.8Hz, 1H), 6.57 (s, 2H), 3 .82 (s, 3H), 3.04 (d, J=6.9Hz, 1H), 2.02 (d, J=10.0Hz, 6H), 1.11 (dd, J=6.8, 2.3Hz, 6H). LCMS: (ESI-MS): [M+H] + =287.0.

[0312] Step 3 Synthesis of compound 39

[0313]

[0314] At 0 ° C, a solution of 38 (550 mg, 1.92 mmol, 1.0 eq) in 4N HCl (5 mL) was added dropwise with a solution of NaNO2 (185 mg, 2.69 mmol, 1.4 eq) in water (1 mL). The mixture was stirred for 30 min, and a mixture of ethyl (2-cyanoacetyl)carbamate (338 mg, 2.16 mmol, 1.125 eq) in pyridine (3 mL) was added. After stirring for 40 minutes, 10 mL of water and 20 mL of EtOAc were added. The organic layer was dried and concentrated to give the desired product 39 (810 mg, crude), which was used directly in the next step without purification. LCMS: (ESI-MS): [M+H] + =453.9.

[0315] Step 4 Synthesis of Compound 40

[0316]

[0317] To a solution of 39 (810 mg, 1.79 mmol, 1.0 eq) in 10 mL of AcOH was added AcONa (733 mg, 8.93 mmol, 5.0 eq) and the mixture was heated to 120 °C. After 1.5 h, the mixture was cooled to 0 °C and diluted with 10 mL of water. The precipitate was collected by filtration to give the desired product 40 (610 mg, crude), which was used directly in the next step without purification. LCMS: (ESI-MS): [M+H] + =408.0.

[0318] Step 5 Synthesis of Compound I6

[0319]

[0320] To a solution of 40 (610 mg, 1.49 mmol, 1.0 eq) in 8 mL of dioxane, HBr (48% aq, 2 mL) was added and heated to 60 ° C and stirred for 3 h. When HPLC showed no starting material, 10 mL of water was added and extracted with 3x10 mL of EA. The organic layers were combined and concentrated. The residue was purified by Prep-HPLC (40% ACN aqueous solution-0.1% TFA as additive) to obtain the desired product I6 (62 mg, 8.2% 3 steps) as a white solid. 1HNMR (400MHz, DMSO) δppm13.03 (s, 1H), 11.10 (brs, 1H), 7.40-7.12 (m, 3H), 6 .30 (d, J=2.0Hz, 1H), 3.08-2.89 (m, 1H), 2.16 (s, 6H), 1.13 (d, J=6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =393.8.

[0321] Example 7

[0322] 2-(3,5-Difluoro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I7).

[0323] Step 1 Synthesis of Compound 41

[0324]

[0325] To a mixture of 5-isopropyl-6-methoxypyridin-3-ol (500 mg, 2.99 mmol, 1.0 eq) and 1,2,3-trifluoro-5-nitrobenzene (529 mg, 2.99 mmol, 1.0 eq) in THF (20 mL) was added t-BuOK (0.77 g, 5.98 mmol, 2.0 eq), and the mixture was stirred overnight at 50 ° C under nitrogen. When HPLC showed no starting material, water (50 mL) was added and extracted with EtOAc (3 x 50 mL). The organic layers were combined and concentrated. The residue was purified by methanol slurry to give the desired product 41 (350 mg, yield: 36%) as a yellow solid. LCMS: (ESI-MS): [M+H] + =324.8.

[0326] Step 2 Synthesis of compound 42

[0327]

[0328] Pd / C (30 mg, 20% w / w) was added to a solution of 41 (200 mg, 0.617 mmol, 1 eq) in EtOAc (10 mL) and the mixture was stirred at room temperature under hydrogen. After HPLC showed the disappearance of the starting material, the solid was removed by filtration, the filtrate was concentrated, and the residue was purified by PE / EA=1 / 1 silica gel column to give the desired product 42 (130 mg, white solid, yield: 71%). LCMS: (ESI-MS): [M+H] + =294.9.

[0329] Step 3 Synthesis of compound 43

[0330]

[0331] At 0 ° C, NaNO2 (23 mg, 0.333 mmol, 1.4 eq) was added dropwise to a solution of 42 (70 mg, 0.238 mmol, 1.0 eq) in 4N HCl (3 mL) in 1.0 mL of water. The mixture was stirred for 30 min and a mixture of (2-cyanoacetyl)ethyl carbamate (41.8 mg, 0.268 mmol, 1.125 eq) and NaOAc (65.88 mg, 0.80 mmol, 3.375 eq) in 2 mL of EtOH was added. After stirring for 40 minutes, EtOH was removed under vacuum, 10 mL of water and 20 mL of DCM were added, and the organic layer was concentrated to obtain the desired product 43 (39 mg, yellow solid, yield: 35.8%).

[0332] Step 4 Synthesis of Compound 44

[0333]

[0334] To a solution of 43 (70 mg, 0.152 mmol, 1.0 eq) in 2 mL of AcOH was added AcONa (62.32 mg, 0.76 mmol, 5.0 eq) and the mixture was heated to 120°C. After 1.5 h, the mixture was cooled to 0°C and diluted with 10 mL of water, and the precipitate was collected by filtration to give the desired product 44 (60 mg, white solid, 95% yield). LCMS: (ESI-MS): [M+H] + =415.8.

[0335] Step 5 Synthesis of Compound I7

[0336]

[0337] To the solution of 44 (60mg, 0.144mmol, 1.0eq) in 2mL dioxane, add HBr (1.2ml, 0.72mmol, 5.0eq, 48%aq) and be heated to 60 ℃ and stir 3 hours.When HPLC shows no starting material, add 10mL water and extract with DCM (3x10mL). Combine organic layers and concentrate. Residue is purified by Prep-HPLC (40% ACN aqueous solution-0.1% TFA as additive) to obtain the required product I7 (3.3mg, white solid, yield: 6.5%). 1HNMR (400MHz, MeOD) δ ppm 7.45 (d, J=8.7Hz, 2H), 7.42 (d, J=3.1Hz, 1H), 6.99 (d, J=3.2Hz, 1H), 3.12 (dt, J=13.7, 6.8Hz, 1H), 1.20 (d, J=6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =402.1.

[0338] Example 8

[0339] 2-(3,5-dichloro-4-((3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I8)

[0340] Step 1 Synthesis of Compound 46

[0341]

[0342] A suspension of 45 (40 g, 160 mmol, 1 eq) and t-BuOK (26.88 g, 240 mmol, 1.5 eq) in THF (400 mL) was stirred at room temperature for 1 h, and then allyl bromide (21.13 g, 174.67 mmol, 1.1 eq) was added dropwise. The mixture was stirred at room temperature overnight. When LCMS showed no starting material, water (500 mL) was added and extracted with EtOAc (3 x 500 mL). The organic layers were combined and concentrated. The crude product was chromatographed on silica gel (PE / EA=20 / 1) to give compound 46 (24 g, 52%) as a colorless liquid. 1 HNMR (400MHz, CDCl3) δppm 8.00 (d, J=2.1Hz, 1H), 7.64 (d, J=2.1Hz, 1H), 5.89 (m, 1H), 5.11 (m, 2H), 5.04 (s, 1H), 4.02-3.97 (m, 2H). LCMS: (ESI-MS): [M+H] + =292.7.

[0343] Step 2 Synthesis of compound 47

[0344]

[0345] To a mixture of 46 (13 g, 44.8 mmol, 1 eq) in MeCN (200 ml) was added Pd(OAc)2 (542 mg, 2.24 mmol, 0.05 eq), tri(o-methylphenyl)phosphine (1.64 g, 5.38 mmol, 0.12 eq) and TEA (13.6 g, 134.4 mmol, 3 eq), and the mixture was heated to reflux and stirred for 5 h. When LCMS showed no starting material, the mixture was filtered through a celite pad, and the filtrate was concentrated to give the crude product, which was purified by silica gel chromatography (PE / EA=15 / 1) to give 47 (4 g, 42%) as a white solid. LCMS: (ESI-MS): [M+H] + =212.8.

[0346] Step 3 Synthesis of compound 48

[0347]

[0348] At room temperature, (Boc)2O (1.74 g, 8 mmol, 1.2 eq) was added to a solution of 47 (1.4 g, 6.67 mmol, 1 eq), DMAP (81.4 mg, 0.67 mmol, 0.1 eq) and TEA (1.35 g, 13.34 mmol, 2 eq) in dichloromethane (20 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and separated in DCM (50 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried (MgSO4) and evaporated to dryness to give 48 (1.2 g, 58%) as a white solid. 1 HNMR (400MHz, CDCl3) δppm 8.44 (d, J=2.2Hz, 1H), 7.86 (d, J=2.2Hz, 1H), 7.34 (d, J=1.1Hz, 1H), 2.16 (d, J=1.2Hz, 3H), 1.58 (s, 9H). LCMS: (ESI-MS): [M+H] + =313.0.

[0349] Step 4 Synthesis of Compound 49

[0350]

[0351] To a solution of 48 (3.5 g, 11.3 mmol, 1 eq) in dioxane (40 mL) was added KOAc (3.32 mg, 33.8 mmol, 3 eq), bisvaleryl diboron (8.6 g, 33.8 mmol, 3 eq) and Pd(dppf)Cl2 (461 mg, 5.65 mmol, 0.05 eq). Nitrogen was passed through the mixture three times and stirred at 80 ° C overnight. The reaction was then cooled to room temperature and filtered through a celite pad, and the filtrate was concentrated to give the crude product 49 (5.5 g, crude), which did not require further purification. LCMS: (ESI-MS): [M+H] + =276.1.

[0352] Step 5 Synthesis of Compound 50

[0353]

[0354] A suspension of sodium perborate tetrahydrate (8.33 g, 54.2 mmol, 3 eq) in H2O (100 mL) was cooled to 0°C and a solution of 49 in THF (10 mL) was added dropwise. After 2 h, the reaction was complete and filtered through a celite pad. The filtrate was extracted with EtOAc (3 x 100 mL). The organic phase was concentrated to give the crude product 50. LCMS: (ESI-MS): [M+H] + =248.9.

[0355] Step 6 Synthesis of Compound 51

[0356]

[0357] To a mixture of 50 (1.7 g, 6.88 mmol, 1.0 eq) and 1,3-dichloro-2-fluoro-5-nitrobenzene (1.45 g, 6.88 mmol, 1.0 eq) in acetone (20 mL) was added K2CO3 (1.89 g, 13.76 mmol, 2.0 eq). The mixture was stirred at 50 ° C under nitrogen for 4 h. When HPLC showed no starting material, water (50 mL) was added to the reaction and the mixture was extracted with EtOAc (3x50 mL). The organic layers were combined and concentrated. The crude product was chromatographed on silica gel (PE / EA=3 / 1) to give the desired product 51 (2.2 g, yield: 73%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δppm 8.26 (s, 2H), 8.15 (d, J=2.6Hz, 1H), 7.38 (s, 1H), 7.11 (d, J=2.7Hz, 1H), 2.12 (s, 3H), 1.58 (s, 9H). LCMS: (ESI-MS): [M+H] + =439.7.

[0358] Step 7: Synthesis of compound 52

[0359]

[0360] To a solution of 51 (1 g, 2.29 mmol, 1 eq) in EtOAc (15 mL) was added PtO2 (0.1 g) and the mixture was stirred at room temperature under hydrogen. After HPLC showed the disappearance of the starting material, the solid was removed by filtration and the filtrate was concentrated to give the desired product 52 (900 mg, yield: 95%) as a white solid. LCMS: (ESI-MS): [M+H] + =409.8;

[0361] Step 8: Synthesis of compound 53

[0362]

[0363] To a solution of 52 (400 mg, 0.98 mmol, 1.0 eq) in 4N HCl (10 mL) was added a solution of NaNO2 (94.7 mg, 1.37 mmol, 1.4 eq) in water (1.0 mL) at 0 °C. The mixture was stirred for 30 min and a mixture of ethyl (2-cyanoacetyl)carbamate (172 mg, 1.103 mmol, 1.125 eq) in pyridine (2.0 mL) was added. After stirring overnight, water (10 mL) and EtOAc (20 mL) were added. The organic layer was dried and concentrated to give the desired product 53 (400 mg, crude), which was used directly in the next step. LCMS: (ESI-MS): [M+H] + =476.7.

[0364] Step 9 Synthesis of Compound I8

[0365]

[0366] To a solution of 53 (400 mg, 0.842 mmol, 1.0 eq) in AcOH (10 mL) was added NaOAc (345 mg, 4.20 mmol, 5.0 eq) and the mixture was heated to 120° C. After 1.5 h, the mixture was cooled to 0° C. and diluted with water (10 mL), and the precipitate was collected by filtration to give the crude product (380 mg, crude), which was purified by Prep-HPLC (35% ACN in water-0.1% TFA as an additive) to give the desired product I8 (91 mg, yield: 25%) as a white solid. 1HNMR (400MHz, DMSO) δppm 13.30 (s, 1H), 11.38 (s, 1H), 8.02 (t, J = 12.3Hz, 1H), 7.82 (s, 2H), 7.41-7.21 (m, 2H), 2.17 (s, 3H). LCMS: (ESI-MS): [M+H] + =428.9.

[0367] Example 9

[0368] 2-(4-((1H-Pyrrolo[2,3-b]pyridin-5-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I9).

[0369] Step 1: Synthesis of compound 55

[0370]

[0371] To a solution of 54 (4.8 g, 35.5 mmol, 1 eq) and DMAP (433 mg, 3.55 mmol, 0.1 eq) in DCM (50.0 mL) was added (Boc) 2 O (23.25 g, 106.7 mmol, 3 eq), which was then stirred at room temperature for 4 h. The reaction mixture was then concentrated under reduced pressure. The residue was dissolved in methanol (150 mL), and potassium carbonate (24.5 g, 177.5 mmol, 5 eq) was added, and then stirred at room temperature for 4 hours. Acetic acid (9.0 mL) was added to the mixture to neutralize, and then water was added, and then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (PE / EA=1 / 1) to give 55 (4 g, 47%). 1 HNMR (400MHz, DMSO) δppm 11.29 (s, 1H), 7.83 (d, J=2.5Hz, 1H), 7.34 (t, J=2.9Hz, 1H), 6.26 (d, J=2.2Hz, 1H), 1.89 (s, 9H). LCMS: (ESI-MS): [M+H] + =235.1.

[0372] Step 2: Synthesis of compound 56

[0373]

[0374] To a mixture of 55 (2.0 g, 8.5 mmol, 1.0 eq) and 1,3-dichloro-2-fluoro-5-nitrobenzene (1.79 g, 8.5 mmol, 1.0 eq) in THF (40 mL) was added t-BuOK (1.91 g, 17 mmol, 2.0 eq). The mixture was stirred at 50 ° C under nitrogen overnight. When HPLC showed no starting material, water (50 mL) was added to the mixture and then extracted with EtOAc (3x50 mL). The organic layers were combined and concentrated. The residue was purified by silica gel column (PE / EA=100 / 1) to give the desired product 56 (1.3 g, yellow solid, yield: 36%). LCMS: (ESI-MS): [M+H] + =425.6.

[0375] Step 3: Synthesis of compound 57

[0376]

[0377] To a solution of 56 (1.2 g, 2.83 mmol, 1 eq) in EtOAc (25 mL) was added Pd / C (0.2 g, 20% w / w) and the mixture was stirred at room temperature under hydrogen. After HPLC showed the disappearance of the starting material, the precipitate was removed by filtration and the filtrate was concentrated. The residue was purified by silica gel chromatography to give the desired product 57 (180 mg, white solid, yield: 16%). LCMS: (ESI-MS): [M+H] + =395.8.

[0378] Step 4: Synthesis of compound 58

[0379]

[0380] To a solution of 57 (180 mg, 0.456 mmol, 1.0 eq) in 4N HCl (5 mL) was added a solution of NaNO2 (46 mg, 0.667 mmol, 1.4 eq) in 1.0 mL of water at 0 ° C. The mixture was stirred for 30 min and a mixture of ethyl (2-cyanoacetyl)carbamate (83.67 mg, 0.536 mmol, 1.125 eq) in pyridine (1.5 mL) was added. After stirring for 40 minutes, water (10 mL) and EtOAc (20 mL) were added. The organic layer was dried and concentrated to give the desired product 58 (100 mg, crude), which was used directly in the next step. LCMS: (ESI-MS): [M+H] + =462.9.

[0381] Step 5: Synthesis of Compound I9

[0382]

[0383] To a solution of 58 (100 mg, 0.218 mmol, 1.0 eq) in AcOH (10 mL) was added NaOAc (89.13 mg, 1.08 mmol, 5.0 eq) and the mixture was heated to 120 ° C. After 1.5 h, the reaction mixture was cooled to 0 ° C and diluted with water (30 mL) and extracted with EtOAc (3x30 mL). The organic layer was dried and concentrated to give a crude product (30 mg), which was purified by Prep-HPLC (35% ACN in water-0.1% TFA as an additive) to give the desired product I9 (1.9 mg, white solid, yield: 2.1%). 1 HNMR (400MHz, MeOD) δppm 8.03 (s, 1H), 7.80 (s, 2H), 7.43-7.40 (m, 2H), 6.43 (d, J = 3.4Hz, 1H). LCMS: (ESI-MS): [M+H] + =414.7.

[0384] Example 10

[0385] 2-(3-Chloro-5-fluoro-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I10)

[0386] Step 1: Synthesis of compound 59

[0387]

[0388] To a mixture of 5-isopropyl-6-methoxypyridine-3-ol (500 mg, 2.97 mmol, 1.0 eq) and 1-chloro-2,3-difluoro-5-nitrobenzene (574 mg, 2.97 mmol, 1.0 eq) in acetone (10 mL) was added K2CO3 (821 mg, 5.95 mmol, 2.0 eq) at room temperature. The mixture was stirred at 50 ° C for 2 h. When LCMS showed no starting material, 50 mL of water was added and extracted with EtOAc (3x50 mL). The organic layers were combined and concentrated. The residue was purified by silica gel column PE / EA=100 / 1 to give the desired product 59 (830 mg, yellow solid, yield: 82%). 1HNMR (400MHz, CDCl3) δppm8.22–8.11 (m, 1H), 7.93 (dd, J=9.6, 2.6Hz, 1H), 7.52 (d, J=2.9Hz, 1H), 7.13 (d, J=2.8Hz, 1H), 3.86 (s, 3H), 3.09 (dt, J=13.8, 6.9Hz, 1H), 1.13 (d, J=6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =340.8.

[0389] Step 2: Synthesis of compound 60

[0390]

[0391] To a solution of 59 (830 mg, 2.44 mmol, 1 eq) in EtOAc (10 mL) was added PtO2 (0.16 g, 20% w / w) and the mixture was stirred at room temperature under hydrogen. After LCMS showed the disappearance of the starting material, the solid was removed by filtration and the filtrate was concentrated to give the desired product 60 (640 mg, black oil, yield: 84%). 1 HNMR (400MHz, CDCl3) δppm7.47 (d, J=2.9Hz, 1H), 7.10 (d, J=2.9Hz, 1H), 6.52-6.43 (m, 1 H), 6.33 (dd, J=11.4, 2.6Hz, 1H), 3.83 (s, 3H), 3.13-2.98 (m, 1H), 1.12 (d, J=6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =311.0.

[0392] Step 3: Synthesis of compound 61

[0393]

[0394] To a solution of 60 (350 mg, 1.13 mmol, 1.0 eq) in 4N HCl (5 mL) was added a solution of NaNO2 (109 mg, 1.58 mmol, 1.4 eq) in 2.0 mL of water at 0 ° C. The mixture was stirred for 30 min and a mixture of ethyl (2-cyanoacetyl)carbamate (198.4 mg, 1.27 mmol, 1.125 eq) in pyridine (2 mL) was added. After stirring for 40 minutes, LCMS showed that the starting material disappeared. The mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was dried and concentrated to give the desired product 61 (430 mg, crude product), which was used directly in the next step. LCMS: (ESI-MS): [M+H]+ =478.0.

[0395] Step 4: Synthesis of compound 62

[0396]

[0397] To a solution of 61 (430 mg, 0.9 mmol, 1.0 eq) in 5 mL of AcOH was added AcONa (369.6 mg, 4.5 mmol, 5.0 eq) and the mixture was heated to 120 °C. After 1.5 h, LCMS showed that the starting material disappeared. The mixture was cooled to 0 °C and diluted with water (10 mL), and the precipitate was collected by filtration to give the desired product 62 (460 mg, crude), which was used directly in the next step without purification. LCMS: (ESI-MS): [M+H] + =431.8

[0398] Step 5: Synthesis of compound I10

[0399]

[0400] To a solution of 62 (460 mg, 1.06 mmol, 1.0 eq) in dioxane (8 mL) was added HBr (2 mL, 48% aq). The reaction mixture was heated to 60 ° C and stirred for 5 hours. When HPLC showed that there was no starting material, the mixture was diluted with water (10 mL) and extracted with EtOAc (3x10 mL). The organic layers were combined and concentrated. The residue was purified by Prep-HPLC (40% ACN aqueous solution-0.1% TFA as additive) to obtain the desired product I10 (81 mg, red solid, three-step yield: 17%). 1 HNMR (400MHz, DMSO) δppm 13.24 (s, 1H), 7.64-7.60 (m, 2H), 7.29 (d, J=3.1Hz, 1H), 6.93 (d, J=2.8Hz, 1H), 3.04-2.94 (m, 1H), 1.12 (d, J=6.9Hz, 6H). LCMS: (ESI-MS): [M+H] + =417.9.

[0401] Embodiment 11

[0402] 2-(3,5-dichloro-4-((5-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I11)

[0403] Step 1: Synthesis of compound 63

[0404]

[0405] To a mixture of 3-bromo-2-methoxypyridine (20 g, 0.11 mmol, 1.0 eq), cyclopropylboronic acid (13.7 g, 0.16 mmol, 1.5 eq) and KCO (73.4 g, 0.53 mmol, 5.0 eq) in DME (200 mL) and HO (40 mL) was added Pd (dppf) Cl-CHCl (8.68 g, 0.01 mmol, 0.1 eq) and the mixture was charged with N three times and stirred overnight at 80 ° C under nitrogen. After TLC showed that the starting material disappeared, the mixture was cooled to room temperature and water (100 ml) was added. The mixture was extracted with EtOAc (4x100 mL), the organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (PE) to obtain the desired product 63 (11.8 g, yield: 74%) as a brown oil. 1 HNMR (400MHz, CDCl3) δppm7.89 (dd, J=4.9, 1.4Hz, 1H), 7.03 (dd, J=7.3, 1.1Hz, 1H), 6.71 (dd, J=7.2 , 5.0Hz, 1H), 3.92 (s, 3H), 1.99 (ddd, J=8.4, 5.1, 3.2Hz, 1H), 0.92-0.82 (m, 2H), 0.63-0.48 (m, 2H). LCMS: [M+1]=149.9.

[0406] Step 2: Synthesis of compound 64

[0407]

[0408] At room temperature, Br2 (6.28 g, 39.26 mmol, 0.9 eq) was added to a solution of 63 (6.5 g, 43.6 mmol, 1.0 eq) and NaOAc (7.87 g, 95.97 mmol) in AcOH (70 mL, 2.2 eq), and the mixture was stirred for 30 min. After HPLC showed no starting material, water (300 mL) was added, and the mixture was extracted with EtOAc (4x100 mL) and washed with sodium bicarbonate solution. The organic layers were combined and concentrated. The residue was purified by silica gel column chromatography (PE) to obtain 3.9 g of the desired product 64 in an oily state, with a yield of 39%. 1HNMR (400MHz, CDCl3) δppm8.00 (d, J=2.3Hz, 1H), 7.18 (d, J=2.3Hz, 1H), 3.97 (s, 3H), 2.08-2.01 (m, 1H), 1.09–0.90 (m, 2H), 0.75–0.59 (m, 2H). LCMS: [M+1]=227.8.

[0409] Step 3: Synthesis of compound 65

[0410]

[0411] To a solution of 64 (2 g, 8.7 mmol, 1.0 eq), KOAc (2.58 mL, 26.3 mmol, 3.0 eq) and bisvaleryl diboron (6.68 g, 26.3 mmol, 3.0 eq) in anhydrous dioxane (20 mL) was added Pd(dppf)Cl2-CH2Cl2 (358 mg, 0.44 mmol, 0.05 eq). The mixture was stirred at 80 °C under nitrogen overnight. After LCMS showed no starting material, the solid was filtered off and washed with EtOAc (3x20 mL), the organic layers were combined and concentrated to give the desired product 65 (2.4 g, crude), which was used directly in the next step. LCMS: [M+1]=276.1.

[0412] Step 4: Synthesis of compound 66

[0413]

[0414] At 0 ° C, a solution of 65 (2.4 g, crude product) in THF (30 mL) was added dropwise to a solution of sodium perborate tetrahydrate (4.1 g, 26.64 mmol, 3.0 eq) in water (40 mL). The mixture was then stirred at room temperature for 3 h. After LCMS showed no starting material, the solid was filtered off and the filtrate was extracted with EtOAc (4x30 mL). The organic layers were combined and concentrated. The residue was purified by flash chromatography (C18 column, 5%-90% ACN aqueous solution) to obtain the desired product 66 (1.0 g, brown colloid, two-step yield: 69%). 1 HNMR (400MHz, CDCl3) δppm7.52 (d, J=2.4Hz, 1H), 6.66 (d, J=2.4Hz, 1H), 3.88 (s, 3H), 2.06-1.87 (m, 1H), 0.96-0.81 (m, 2H), 0.64-0.48 (m, 2H). LCMS: [M+1]=165.9.

[0415] Step 5: Synthesis of compound 67

[0416]

[0417] To a mixture of 66 (1.0 g, 6.06 mmol, 1.0 eq) and 1,3-dichloro-2-fluoro-5-nitrobenzene (1.27 g, 6.06 mmol, 1.0 eq) in acetone (20 mL) was added K2CO3 (1.67 g, 12.12 mmol, 2.0 eq) at room temperature. The mixture was stirred overnight at 50 ° C under nitrogen. When LCMS showed no starting material, water (50 mL) was added and extracted with EtOAc (3x50 mL). The organic layers were combined and concentrated. The residue was purified by silica gel column (PE / EA=50 / 1) to give the desired product 67 (1.3 g, yellow solid, yield: 61%). 1 HNMR (400MHz, DMSO) δppm 8.52 (s, 2H), 7.51 (d, J = 2.9Hz, 1H), 7.04 (d, J = 2.9H) z, 1H), 3.86 (s, 3H), 2.12-1.90 (m, 1H), 1.08-0.85 (m, 2H), 0.79-0.58 (m, 2H). LCMS: (ESI-MS): [M+H] + =356.7.

[0418] Step 6: Synthesis of compound 68

[0419]

[0420] To a solution of 67 (620 mg, 1.75 mmol, 1 eq) in EtOAc (10 mL) was added PtO2 (0.12 g, 20% w / w) and the mixture was stirred at room temperature under hydrogen. After LCMS showed the disappearance of the starting material, the solid was removed by filtration and the filtrate was concentrated to give the desired product 68 (530 mg crude, yellow solid). 1 HNMR (400MHz, DMSO) δppm7.37 (d, J=2.9Hz, 1H), 6.92 (d, J=2.8Hz, 1H), 6.75 (s, 2H), 5.71 (s, 2H), 3.89 (s, 3H), 2.04 (dd, J=9.4, 4.0Hz, 1H), 1.05-0.88 (m, 2H), 0.78-0.61 (m, 2H). LCMS: (ESI-MS): [M+H] + =327.0.

[0421] Step 7: Synthesis of compound 69

[0422]

[0423] To a solution of 68 (530 mg, 1.63 mmol, 1.0 eq) in 4N HCl (10 mL) was added a solution of NaNO2 (158 mg, 2.29 mmol, 1.4 eq) in 1.0 mL of water at 0 ° C. The mixture was stirred for 30 min and a solution of ethyl (2-cyanoacetyl)carbamate (287.5 mg, 1.84 mmol, 1.125 eq) in pyridine (3 mL) was added dropwise. After stirring for 40 minutes, LCMS showed that the starting material disappeared; the mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was dried and concentrated to give the desired product 69 (340 mg, crude), which was used directly in the next step without purification. LCMS: (ESI-MS): [M+H] + =493.7.

[0424] Step 8: Synthesis of compound 70

[0425]

[0426] To a solution of 69 (340 mg, 0.691 mmol, 1.0 eq) in AcOH (5 mL) was added AcONa (283 mg, 3.45 mmol, 5.0 eq). The mixture was heated to 120 ° C. After 1.5 h, LCMS showed that the starting material disappeared. The mixture was cooled to 0 ° C and diluted with water (10 mL). The precipitate was collected by filtration to give the desired product 70 (400 mg, crude), which was used directly in the next step without purification. LCMS: (ESI-MS): [M+H] + =447.7

[0427] Step 9: Synthesis of compound I11

[0428]

[0429] To a solution of 70 (400 mg, 0.928 mmol, 1.0 eq) in 8 mL of dioxane, HBr (2 mL, 48% aq) was added, and heated to 60 ° C, and stirred for 3 hours. When HPLC showed no starting material, water (10 mL) was added and extracted with EtOAc (3x10 mL). The organic layers were combined and concentrated. The residue was purified by Prep-HPLC (60% ACN aqueous solution-0.1% TFA as additive) to obtain the desired product I11 (47 mg, yellow-white solid, three-step yield: 6.6%). 1HNMR (400MHz, DMSO-d6) δppm13.26 (s, 1H), 11.27 (s, 1H), 7.77 (s, 2H), 7.02 (d, J=3.1Hz, 1H), 6.64 (s, 1H), 1.99 (dd, J=9.4, 4.2Hz, 1H), 0.96-0.78 (m, 2H), 0.72 (q, J=6.0Hz, 2H). LCMS: (ESI-MS): [M+H] + =433.7.

[0430] Example 12

[0431] 2-(3,5-dichloro-4-((3-methyl-1H-indol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I12)

[0432] Step 1: Synthesis of compound 72

[0433]

[0434] Under stirring at 0°C, oxalyl chloride (12.12 g, 95.5 mmol, 0.71 eq) was added dropwise to DMF (200 mL). The mixture was allowed to warm to room temperature and stirred for 1 hour. After cooling to 0°C, a solution of 71 (30 g, 134.5 mmol, 1 eq) in DMF (150 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for 5 hours, and then sodium hydroxide solution (25 mL) was added. The reaction mixture was stirred at 100°C for 10 minutes. After cooling to room temperature, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by recrystallization (using petroleum ether and ethyl acetate as extraction agents) to obtain an aldehyde product (12 g, crude product). A solution of the obtained aldehyde product (12 g, crude product) in THF (60 mL) was added dropwise to a mixture of LiAlH4 (3.8 g, 10 mmol) in redistilled anhydrous THF (150 mL) in a dry round flask. After the mixture was stirred at room temperature overnight, water (3.8 mL) was carefully added and the reaction mixture was stirred for 5 minutes. The obtained solid was removed by filtration and washed with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (PE: EA = 3: 1) to give 72 (5.2 g, 16.3%). 1HNMR (400MHz, CDCl3) δppm7.71 (s, 1H), 7.42 (d, J=7.4Hz, 2H), 7.32 (t, J=7.4Hz, 2H), 7.25 (t, J=7.2Hz, 1 H), 7.18 (s, 1H), 7.04 (d, J=2.3Hz, 1H), 6.86 (dd, J=10.2, 3.7Hz, 2H), 5.04 (d, J=7.6Hz, 2H), 2.22 (s, 3H). LCMS: (ESI-MS): [M+H] + =238.2.

[0435] Step 2: Synthesis of compound 73

[0436]

[0437] To a solution of 72 (5.2 g, 21.9 mmol, 1 eq), DMAP (267 mg, 2.19 mmol, 0.1 eq) and TEA (4.43 g, 43.88 mmol, 2 eq) in dichloromethane (50 ml) was added (Boc)2O (5.73 g, 26.28 mmol, 1.2 eq) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and distributed between DCM (100 ml) and water (50 ml). The organic layer was washed with brine (50 ml), dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel (PE:EA=5:1) to give 73 (5.6 g, 75.7%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δppm7.92 (s, 1H), 7.39 (d, J=7.3Hz, 2H), 7.31 (t, J=7.4Hz, 2H), 7. 24 (t, J=6.5Hz, 2H), 6.98–6.81 (m, 2H), 5.04 (d, J=5.9Hz, 2H), 2.14 (s, 3H), 1.57 (s, 9H). LCMS: (ESI-MS): [M+H] + =338.1.

[0438] Step 3: Synthesis of compound 74

[0439]

[0440] To a solution of 73 (5 g, 14.8 mmol, 1.0 eq) in MeOH (50 mL) was added Pd / C (0.5 g) and the mixture was stirred at room temperature under hydrogen overnight. After HPLC showed no starting material was present, the solid was filtered off, the filtrate was concentrated, and the residue was purified by flash chromatography on silica gel (PE:EA=1:1) to give the desired product 74 (2 g, 54.5%) as a gray solid. 1 HNMR (400MHz, CDCl3) δppm7.88 (s, 1H), 7.25 (s, 1H), 6.83 (d, J=2.4Hz, 1H), 6.75 (dd, J=8.8, 2.5Hz, 1H), 2.12 (d, J=1.2Hz, 3H), 1.57 (s, 9H). LCMS: (ESI-MS): [M+H] + =248.1.

[0441] Step 4: Synthesis of compound 75

[0442]

[0443] To a mixture of 74 (1.0 g, 4 mmol, 1.0 eq) and 1,3-dichloro-2-fluoro-5-nitrobenzene (850 mg, 4.04 mmol, 1.0 eq) in acetone (20 mL) was added K2CO3 (1.12 g, 8.1 mmol, 2.0 eq). The mixture was stirred at 50 ° C under nitrogen for 4 h. When HPLC showed no starting material, water (50 mL) was added and the mixture was extracted with EtOAc (3x50 mL). The organic layers were combined and concentrated. The residue was purified by flash chromatography on silica gel (PE: EA = 10: 1) to give the desired product 75 (1.4 g, yield: 79.1%) as a yellow solid. 1 HNMR (400MHz, CDCl3) δppm8.25 (s, 2H), 8.05–7.89 (m, 1H), 7.30 (s, 1H), 6.77 (dt, J=8.8, 2.2Hz, 2H), 2.11 (d, J=1.1Hz, 3H), 1.58 (d, J=6.7Hz, 9H).

[0444] Step 5: Synthesis of compound 76

[0445]

[0446] To a solution of 75 (700 mg, 1.6 mmol, 1 eq) in EtOAc (10 mL) was added PtO2 (70 mg) and the mixture was stirred at room temperature under hydrogen. After HPLC showed the disappearance of the starting material, the solid was removed by filtration and the filtrate was concentrated to give the desired product 76 (550 mg, white solid, yield: 84%). 1 HNMR (400MHz, CDCl3) δppm7.93 (d, J=13.8Hz, 1H), 7.26 (s, 1H), 6.86–6.73 (m, 2H), 6.70 (s, 2H), 2.12 (t, J=4.5Hz, 3H), 1.57 (d, J=7.1Hz, 9H). LCMS: (ESI-MS): [M+H] + =407.0.

[0447] Step 6: Synthesis of compound 77

[0448]

[0449] At 0°C, a solution of 76 (670 mg, 1.64 mmol, 1.0 eq) in 4N HCl (10 mL) was added dropwise with a solution of NaNO2 (159 mg, 2.3 mmol, 1.4 eq) in 1.0 mL of water. The mixture was stirred for 30 minutes, and a mixture of ethyl ((2-cyanoacetyl)carbamate (289.3 mg, 1.85 mmol, 1.125 eq) in pyridine (2 mL) was added. After stirring overnight, water (10 mL) and EtOAc (20 mL) were added. The organic layer was dried and concentrated to give the desired product 77 (550 mg, crude), which was used directly in the next step without further purification. 1 HNMR (400MHz, CDCl3) δppm7.93 (d, J=13.8Hz, 1H), 7.26 (s, 1H), 6.86–6.73 (m, 2H), 6.70 (s, 2H), 2.12 (t, J=4.5Hz, 3H), 1.57 (d, J=7.1Hz, 9H). LCMS: (ESI-MS): [M+H] + =571.7.

[0450] Step 7: Synthesis of compound I12

[0451]

[0452] To a solution of 77 (550 mg, 0.96 mmol, 1.0 eq) in AcOH (10 mL) was added NaOAc (394 mg, 4.8 mmol, 5.0 eq) and the mixture was heated to 120° C. After 1.5 h, the mixture was cooled to 0° C. and diluted with water (10 mL), and the precipitate was collected by filtration to give the crude product (780 mg), which was purified by Prep-HPLC (30% ACN in water-0.1% TFA as an additive) to give the desired product I12 (35 mg, red solid, yield: 5%). 1 HNMR (400MHz, MeOD) δppm7.78 (s, 2H), 7.28 (d, J=9.6Hz, 1H), 7.02 (s, 1H), 6.83–6.73 (m, 2H), 2.21 (s, 3H). LCMS: (ESI-MS): [M+H] + =427.7.

[0453] Embodiment 13

[0454] 2-(4-((1H-benzo[d]imidazol-5-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I13)

[0455] Compound I13 was synthesized by a method similar to that of compound I12.

[0456] Embodiment 14

[0457] 2-(3,5-dichloro-4-((3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I14)

[0458] Compound I14 was synthesized by a method similar to that of compound I12.

[0459] Embodiment 15

[0460] 2-(3,5-dichloro-4-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I15)

[0461] Step 1: Synthesis of I15-2:

[0462]

[0463] At 0°C, BTC (6.5 g, 21.90 mmol) was added to a solution of compound I15-1 (3 g, 21.74 mmol) and Et3N (3.3 g, 32.67 mmol) in DCM (30 mL). The resulting mixture was stirred at room temperature for 6 hours, then diluted with water, the pH was adjusted to 8 with Na2CO3, extracted with EA (30 mLx2), and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH=10 / 1) to give compound I15-2 (2 g, 56% yield) as a yellow solid. MS Calcd: 164; MS Found: 165 [M+H] + .

[0464] Step 2: Synthesis of I15-3:

[0465]

[0466] To a solution of compound I15-2 (2 g, 12.20 mmol) in DCM (40 mL) was added BBr3 (15 g, 59.88 mmol) dropwise at 0°C. The reaction mixture was stirred at 40°C. 0 C. Stir for 8 hours, adjust pH to 8 with Na2CO3 and concentrate. Dissolve the product in THF, filter and concentrate to obtain compound I15-3 (1.7 g, yield: 94%) as a brown solid. MS Calcd: 150; MS Found: 151 [M+H] + .

[0467] Step 3: Synthesis of I15-4:

[0468]

[0469] 1,3-dichloro-2-fluoro-5-nitrobenzene (2.5 g, 11.90 mmol) and K2CO3 (2.5 mg, 18.12 mmol) were added to a solution of compound I15-3 (1.8 g, 12 mmol) in DMF (20 mL). The resulting mixture was stirred at 50 ° C for 1 hour, the reaction was diluted with H2O (20 mL) and extracted with EA (30 mLx2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH=10 / 1) to give compound I15-4 (2.1 g, yield: 52%) as a yellow solid. MS Calcd: 339; MS Found: 340 [M+H] + .

[0470] Step 4: Synthesis of I15-5:

[0471]

[0472] To a solution of compound I15-4 (1.8 g, 5.3 mmol) in MeOH (40 mL) and water (5 mL) was added Zn (3.5 g, 53.85 mmol) and NH4Cl (2.8 g, 52.83 mmol). The reaction mixture was stirred at 80 ° C for 3 hours, then filtered and concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH = 15 / 1) to give compound I15-5 (1.5 g, yield: 91%) as a yellow solid. MS Calcd: 309; MS Found: 310 [M + H] + .

[0473] Step 5: Synthesis of I15-6:

[0474]

[0475] To a solution of compound I15-5 (500 mg, 1.62 mmol) in HOAc / HCl=18 mL / 3 mL was added NaNO2 (167 mg, 2.42 mmol) at 5-10°C. The reaction mixture was stirred at 5-10°C for 30 minutes. Ethyl (2-cyanoacetyl)carbamate (379 mg, 2.42 mmol) was then added followed by a solution of NaOAc (398 mg, 4.85 mmol) in H2O. The reaction mixture was stirred at 5-10°C for 3 hours. The reaction was diluted with H2O (20 mL), allowed to stand for 2 days, a solid precipitated, filtered, and concentrated to give compound I15-6 (380 mg, yield: 49%) as a yellow solid. MS Calcd: 476; MS Found: 477 [M+H] + .

[0476] Step 6: Synthesis of I15:

[0477]

[0478] To a solution of compound I15-6 (300 mg, 0.63 mmol) in DMF (15 mL) was added KOAc (185 mg, 1.89 mmol). The reaction mixture was stirred at 120 ° C for 3 hours, then filtered and concentrated. The residue was purified by prep-HPLC to give I15 (59.9 mg, yield: 22%) as a white solid. 1HNMR (400MHz, DMSO-d6) δ: 13.27 (s, 1H), 10.56 (s, 1H), 10.50 (s, 1H), 7.81 (s, 2H), 6.88 (d, J = 8.4Hz, 1H), 6.47-6.45 (m, 1H), 6.42 (d, J = 2.0Hz, 1H), MS Calcd: 430; MS Found: 431[M+H] + .

[0479] Example 16

[0480] 2-(4-((1H-indol-5-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I16)

[0481] Compound I16 was synthesized by a method similar to compound I12.

[0482] Embodiment 17

[0483] 2-(4-((1H-indol-6-yl)oxy)-3,5-dichlorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I17)

[0484] Compound I17 was synthesized by a method similar to that of compound I12.

[0485] Embodiment 18

[0486] 2-(3,5-dichloro-4-((2-oxoindolin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I18)

[0487] Compound I18 was synthesized by a method similar to compound I12.

[0488] Embodiment 19

[0489] 2-(3,5-dichloro-4-((3,3-dimethyl-2-oxoindolin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I19)

[0490] Compound I19 was synthesized by a method similar to compound I12.

[0491] Embodiment 20

[0492] 2-(3,5-dichloro-4-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I20)

[0493] Step 1: Synthesis of I20-2:

[0494]

[0495] To a solution of compound I20-1 (0.50 g, 3.10 mmol) in THF (10 mL) was added CDI (0.993 g, 6.2 mmol) and Et3N (0.626 g, 6.2 mmol). The resulting mixture was stirred at room temperature for 5 hours. The reaction was concentrated and purified by silica gel flash chromatography (PE / EA=1 / 2) to give compound I20-2 (350 mg, yield: 76%) as a white solid. LC-MS (ESI-MS): [MH]+=149.9.

[0496] Step 2: Synthesis of I20-3:

[0497]

[0498] 1,3-dichloro-2-fluoro-5-nitrobenzene (0.695 g, 3.31 mmol) and K2CO3 (0.913 g, 6.62 mmol) were added to a solution of compound I20-2 (0.50 g, 3.31 mmol) in DMF (10 mL). The reaction mixture was stirred at room temperature overnight, diluted with H2O (200 mL) and extracted with EA (200 mLx3). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=1 / 1) to give compound I20-3 (700 mg, yield: 62%) as a white solid. LC-MS (ESI-MS): [MH] + =339.0.

[0499] Step 3: Synthesis of I20-4:

[0500]

[0501] Fe (164 mg, 2.9 mmol) and NH4Cl (160 mg, 2.9 mmol) were added to a solution of compound I20-3 (100 mg, 0.29 mmol) in EtOH (2 mL) and water (1 mL). The reaction mixture was refluxed and stirred for 1.5 hours. The reaction was cooled to room temperature, diluted with H2O (100 mL) and extracted with EA (100 mLx2). The combined organic layer was washed with brine (50 mLx2), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=1 / 1) to give compound I20-4 (70 mg, yield: 78%) as a white solid. LC-MS (ESI-MS): [MH] + =309.

[0502] Step 4: Synthesis of I20:

[0503]

[0504] At 0 ° C, HCl (0.3 mL, 5%) and NaNO2 (27 mg, 0.387 mmol) were added to a solution of compound I20-4 (40 mg, 0.129 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 1 hour. (2-cyanoacetyl) ethyl carbamate (50 mg) was added and the resulting mixture was stirred at room temperature for 2 hours, and the reaction was diluted with H2O (100 mL) and extracted with EA (130 mLx2). The combined organic layer was washed with brine (100 mLx2), dried over Na2SO4, filtered and concentrated. The residue was dissolved in CH3COOH (2 mL), and CH3COONa (100 mg) was added. The resulting mixture was refluxed and stirred for 2 hours. The reaction was cooled to room temperature, diluted with H2O (50 mL) and extracted with EA (150 mLx3). The combined organic layer was washed with brine (50 mLx2), dried over Na2SO4, filtered and concentrated. The residue was purified by pre-HPLC to give compound 120 (7.0 mg, yield: 12.7%) as a white solid. LC-MS (ESI-MS): [MH]+=429.9. 1 HNMR (400MHz, MeOH-d4) δppm: 7.87 (s, 1H), 7.12 (d, J=8.4Hz, 1H), 6.96 (d, J=2.0Hz, 2H), 6.77-6.74 (m, 1H).

[0505] Embodiment 21

[0506] 2-(3,5-dichloro-4-((3-methyl-1H-indol-5-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I21)

[0507] Step 1: Synthesis of I21-2:

[0508]

[0509] Tetrabutylammonium hydrogen sulfate (163.8 g, 0.479 mmol) and fresh finely powdered sodium hydroxide (0.96 g, 23.95 mmol) were added sequentially to a solution of I21-1 (1.00 g, 4.79 mmol) in anhydrous dichloromethane (20 mL). The resulting solution was stirred for 15 minutes, and acetyl chloride (1.6 ml, 23.95 mmol) was added dropwise over 15 minutes. The resulting slurry was stirred vigorously for 2 hours and quenched by adding water. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Flash column chromatography purification (PE / EA: 95 / 5) gave 1-acetyl-3-methylindole (0.81 g, 67.5%) as a white solid.

[0510] Step 2: Synthesis of I21-3:

[0511]

[0512] To a solution of compound I21-2 (0.50g, 1.99mmol) in 1,4-dioxane (10mL), bisvaleryl diboron (758mg, 2.98mmol), CHCOOK (0.390g, 3.98mmol), Pd (PPh) (150mg) were added. The reaction mixture was heated to 100 ° C under nitrogen for 10 hours. The reaction was cooled to room temperature, diluted with H2O (100mL) and extracted with EA (200mLx2). The combined organic layer was washed with brine (50mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=100 / 1) to give compound I21-3 (400mg, yield: 67%) as a white solid.

[0513] Step 3: Synthesis of I21-4:

[0514]

[0515] DPPA (1.98 g, 7.3 mmol) was added to a solution of compound I21-0 (500 mg, 2.43 mmol) in t-BuOH (1 mL) and 1,4-dioxane (5 mL). The reaction mixture was refluxed and stirred for 12 hours. The reaction was then cooled to room temperature, diluted with H2O (50 mL), and extracted with EA (100 mLx2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=1 / 1) to give compound I21-4 (410 mg, yield: 61%) as a dark oil. LC-MS (ESI-MS): [M-55]+=219.7.

[0516] Step 4: Synthesis of I21-5:

[0517]

[0518] NBS (490 mg, 2.72 mmol) and BPO (100 mg) were added to a solution of compound I21-4 (500 mg, 1.818 mmol) in CCl4 (6 mL). The reaction mixture was refluxed for 3 hours. The reaction was diluted with H2O (100 mL) and extracted with EA (200 mLx2). The combined organic layer was washed with brine (50 mLx2), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=10 / 1) to give compound I21-5 (300 mg, yield: 47%) as a white solid.

[0519] Step 5: Synthesis of I21-6:

[0520]

[0521] I21-5 (828 mg, 2.34 mmol), Na2CO3 (0.496 g, 4.68 mmol), Pd(PPh3)4 (100 mg) were added to a solution of compound I21-3 (0.70 g, 2.34 mmol) in Tol (20 mL) and EtOH (4 mL). The reaction mixture was heated to 100 ° C for 5 hours under N2. The reaction was cooled to room temperature, diluted with H2O (100 mL) and extracted with EA (200 mLx2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (PE / EA=5 / 1) to give compound I21-6 (400 mg, yield: 38%) as a white solid. LC-MS (ESI-MS): [M-55]+=390.7.

[0522] Step 6: Synthesis of I21-7:

[0523]

[0524] To a solution of compound I21-6 (100 mg, 0.224 mmol) in DCM (2 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give compound I21-7 (70 mg, yield: 90%) as a black solid.

[0525] Step 7: Synthesis of I21-8:

[0526]

[0527] At 0 ° C, HCl (0.5 mL, 5%) and NaNO2 (80 mg, 1.156 mmol) were added to a solution of compound I21-7 (200 mg, 0.578 mmol) in water (3 mL). The reaction mixture was stirred at room temperature for 1 hour, (2-cyanoacetyl) ethyl carbamate (270 mg, 1.73 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The reaction was diluted with (50 mL) and extracted with EA (50 mLx2). The combined organic layer was washed with brine (10 mLx2), dried over Na2SO4, filtered and concentrated. The residue was dissolved in CH3COOH (2 mL), CH3COONa (30 mg) was added, and the resulting mixture was stirred at reflux for 3 hours. The reaction was cooled to room temperature, diluted with H2O (50 mL) and extracted with EA (100 mLx3). The combined organic layer was washed with brine (20 mLx2), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (PE / EA=1 / 1) to give compound I21-8 (160 mg, yield: 59%) as a white solid. MS Calcd: 467; MS Found: 468 [M+H] + .

[0528] Step 8: Synthesis of I21:

[0529]

[0530] DBU (51.7 mg, 0.34 mmol) was added to a solution of compound I21-8 (80 mg, 0.17 mmol) in MeOH (2 mL). The reaction mixture was stirred at room temperature for 1 hour, diluted with H2O (50 mL) and extracted with EA (100 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by pre-HPLC to give compound I21 (31 mg, yield: 64%) as a yellow solid. LC-MS (ESI-MS): [M+H]+=426.0. 1HNMR (400MHz, DMSO-d6) δppm: 13.2 (br, 1H), 10.67 (s, 1H), 7 .67 (s, 2H), 7.24 (d, J=8.8Hz, 2H), 7.07 (s, 1H), 6.89-6.86 (m, 1H), 4.38 (s, 2H), 2.18 (s, 3H).

[0531] Embodiment 22

[0532] (5-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H)-yl)phenoxy)-3-isopropyl-2-oxopyridin-1(2H)-yl)methyl valine ester (I22)

[0533] Compound I22 was synthesized by a method similar to that of compound I12.

[0534] Embodiment 23

[0535] Sodium (5-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-3-isopropyl-2-oxopyridin-1(2H)-yl)methylphosphonate (I23)

[0536] Compound I23 was synthesized by a method similar to that of compound I12.

[0537] Embodiment 24

[0538] (5-(2,6-dichloro-4-(6-cyano-3,5-dioxo-4,5-dihydro-1,2,4-triazine-2(3H)-yl)phenoxy)-3-isopropyl-2-oxopyridin-1(2H)-yl)acetate (I24)

[0539] Compound 124 was synthesized by a method similar to compound 112.

[0540] Embodiment 25

[0541] 2-(3,5-dichloro-4-((2-isopropyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I25)

[0542] Compound 125 was synthesized by a method similar to compound 112.

[0543] Embodiment 26

[0544] 2-(3,5-dichloro-4-((2-methyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I26)

[0545] Compound 126 was synthesized by a method similar to compound 112.

[0546] Embodiment 27

[0547] 2-(3,5-dichloro-4-((6-isopropyl-5-oxo-4,5-dihydropyrazin-2-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I27)

[0548] Compound 127 was synthesized by a method similar to compound 112.

[0549] Embodiment 28

[0550] 2-(3,5-dichloro-4-((1-isopropyl-2,4-dioxy-1,2,3,4-tetrahydropyrimidin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I28)

[0551] Step 1: Synthesis of I28-2:

[0552]

[0553] To a solution of compound I28-1 (2 g, 14.08 mmol) in DMF (40 mL) was added 2-iodopropane (4.8 g, 28.23 mmol) and K2CO3 (3.9 g, 28.23 mmol). The resulting mixture was stirred at 90 ° C for 24 hours. Then filtered, washed with DMF and concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH=100 / 1) to give compound I28-2 (300 mg, yield: 12%) as a white solid. MS Calcd: 184; MS Found: 185 [M+H] + .

[0554] Step 2: Synthesis of I28-3:

[0555]

[0556] To a solution of compound I28-2 (300 mg, 1.63 mmol) in DCM (8 mL) was added BBr3 (2 g, 7.98 mmol) dropwise at 0°C and stirred at 40 °C. 0 C. and stirred for 10 hours. The pH of the reaction mixture was adjusted to 8 with Na2CO3 and concentrated. The product was dissolved in THF, filtered and concentrated to give compound I28-3 (270 mg, yield: 97%) as a white solid. MS Calcd: 170; MS Found: 171 [M+H] + .

[0557] Step 3: Synthesis of I28-4:

[0558]

[0559] 1,3-dichloro-2-fluoro-5-nitrobenzene (593 mg, 2.82 mmol) and K2CO3 (520 mg, 3.77 mmol) were added to a solution of compound I28-3 (320 mg, 1.88 mmol) in DMF (40 mL). The resulting mixture was stirred at 100 ° C for 2 hours. The reaction was diluted with (20 mL) and extracted with EA (30 mLx2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH=40 / 1) to give compound I28-4 (290 mg, yield: 43%) as a white solid. MS Calcd: 359; MS Found: 360 [M+H] + .

[0560] Step 4: Synthesis of I28-5:

[0561]

[0562] To a solution of compound I28-4 (300 mg, 0.84 mmol) in MeOH (10 mL) and water (1 mL) was added Zn (543 mg, 8.4 mmol) and NH4Cl (443 mg, 8.4 mmol). The reaction mixture was stirred at 80 ° C for 3 hours. Then filtered and concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH = 40 / 1) to give compound I28-5 (270 mg, yield: 98%) as a white solid. MS Calcd: 329; MS Found: 330 [M + H] + .

[0563] Step 5: Synthesis of I28-6:

[0564]

[0565] At 5-10 ° C, NaNO2 (94 mg, 1.36 mmol) was added to a solution of compound I28-5 (300 mg, 0.91 mmol) in HOAc / HCl=6 mL / 1 mL. The reaction mixture was stirred at 5-10 ° C for 30 minutes. Ethyl (2-cyanoacetyl) carbamate (213 mg, 1.36 mmol) was then added, followed by a solution of NaOAc (224 mg, 2.73 mmol) in H2O. The reaction mixture was stirred at 5-10 ° C for 8 hours. The reaction was diluted with H2O (20 mL) and extracted with DCM (30 mLx2), and concentrated to give compound I28-6 (300 mg, yield: 66%) as a yellow solid. MS Calcd: 496; MS Found: 497 [M+H] + .

[0566] Step 6: Synthesis of I28:

[0567]

[0568] To a solution of compound I28-6 (300 mg, 0.60 mmol) in DMF (15 mL) was added KOAc (178 mg, 1.80 mmol). The reaction mixture was stirred at 120 ° C for 3 hours. Then filtered and concentrated. The residue was purified by prep-HPLC to give I28 (31.2 mg, yield: 11%) as a white solid. 1HNMR (400MHz, DMSO-d6) δ: 13.25 (s, 1H), 11.64 (s, 1H), 7.87 (s, 1H), 7.65 (s, 2H), 4.69-4.62 (m, 1H), 1.25 (d, J=6.8Hz, 6H). MSCalcd: 450; MS Found: 451[M+H] + .

[0569] Examples 29 and 30

[0570] 2-(3,5-dichloro-4-((5-isopropyl-6-oxopyrimidin-1(6H)-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I29)

[0571] 2-(3,5-dichloro-4-((5-isopropyl-4-oxopyrimidin-1(4H)-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I30)

[0572] Step 1: Synthesis of I30-2:

[0573]

[0574] At -50 ° C, within 2 minutes, LDA (50 mL, 99.87 mmol, 2M / THF) was added to a solution of I30-1 (10 g, 76.82 mmol) in THF (50 mL), and ethyl formate (8.53 g, 115.2 mmol) was added at this temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with H2O (50 mL) and extracted with EA (50 mL × 2). The combined organic layer was washed with brine (50 mLx2), dried over Na2SO4, filtered and concentrated. The residue was dissolved in 30 mL MeOH, and thiourea (4.55 g, 59.74 mmol) was added. The reaction mixture was stirred at 70 ° C for 4 hours. The reaction was concentrated and purified by silica gel flash chromatography (PE / EA = 5 / 1) to give compound I30-2 (6.0 g, yield: 46%) as a yellow solid. MSCalcd: 170; MS Found: 171[M+H] + .

[0575] Step 2: Synthesis of I30-3:

[0576]

[0577] To a solution of compound I30-2 (3.0 g, 17.6 mmol) in MeOH (30 mL) was added Raney Ni (2 mL, 10%) and the reaction mixture was stirred overnight at 70 ° C under a hydrogen balloon. The reaction mixture was filtered and washed with MeOH (20 mL). The residue was concentrated to give compound I30-3 (1.4 g, yield: 58%) as a yellow solid. MS Calcd: 138; MS Found: 139 [M + H] + .

[0578] Step 3: Synthesis of I30-4 and I30-4a:

[0579]

[0580] 4-(bromomethyl)-3,5-dichloroaniline (1.03g, 2.9mmol) and K2CO3 (1.2g, 8.7mmol) were added to a solution of compound I30-3 (0.4g, 2.9mmol) in DMF (20mL). The resulting mixture was stirred overnight at 100°C under N2. The reaction mixture was cooled to room temperature, diluted with H2O (20mL) and extracted with EA (20mLx3). The combined organic layer was washed with brine (50mLx2), dried over Na2SO4, filtered and concentrated. The residue was purified by reverse phase silica gel flash chromatography (ACN / H2O=5%-95%, 254nm, 30min) to give compound I30-4 (450mg, yield: 38%) and compound I30-4a (350mg, yield: 29%) as a yellow solid. MS Calcd: 412; MS Found: 413[M+H] + . 1 HNMR (I30-4, 400MHz, DMSO-d6) δ: 9.92 (s, 1H), 8.25 (d, J=2.4Hz, 1H), 7.66 (s, 2H), 7. 32(d, J=2.0Hz, 1H), 5.25(s, 2H), 2.78-2.72(m, 1H), 1.48(s, 9H), 1.06-1.03(m, 6H). 1 HNMR (I30-4a, 400MHz, DMSO-d6) δ: 9.83 (s, 1H), 8.05 (s, 1H), 7.75 (s, 1H), 7.6 0 (s, 2H), 5.21 (s, 2H), 2.95-2.84 (m, 1H), 1.48 (s, 9H), 1.12 (d, J=6.8Hz, 6H).

[0581] Step 4: Synthesis of I30-5:

[0582]

[0583] To a solution of compound I30-4 (450 mg, 1.1 mmol) in EA (20 mL) was added HCl / EA (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and washed with Et2O (10 mL). The residue was concentrated to give compound I30-5 (340 mg, yield: 100%) as a yellow solid. MS Calcd: 312; MS Found: 313 [M+H] + .

[0584] Step 5: Synthesis of I30:

[0585]

[0586] At 5-10 ° C, NaNO2 (99.4 mg, 1.44 mmol) was added to a solution of compound I30-5 (300 mg, 0.96 mmol) in HOAc / HCl (6 mL / 1 mL). The reaction mixture was stirred at 5-10 ° C for 30 minutes. Then (2-cyanoacetyl) ethyl carbamate (225 mg, 1.44 mmol) was added followed by a solution of NaOAc (236.2 mg, 2.88 mmol) in H2O (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with H2O (20 mL) and extracted with EA (30 mLx2). The combined organic layers were washed with brine (20 mLx2), dried over Na2SO4, filtered and concentrated. The residue was dissolved in 15 mL DMF and KOAc (282.2 mg, 2.88 mmol) was added. The reaction mixture was stirred at 120 ° C for 2 hours. The reaction was diluted with H2O (20 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give I30 (37 mg, yield: 9%) as a yellow solid. MS Calcd: 433; MS Found: 434 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ: 8.31 (d, J=2.8Hz, 1H), 7.79 (s, 2H), 7.39-7.37 (m, 1H), 5.37 (s, 2H), 2.79-2.71 (m, 1H), 1.05 (d, J=6.8Hz, 6H).

[0587] Step 6: Synthesis of I30-5a:

[0588]

[0589] To a solution of compound I30-4a (264 mg, 1.1 mmol) in EA (20 mL) was added HCl / EA (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and washed with Et2O (10 mL). The residue was concentrated to give compound I30-5a (200 mg, yield: 100%) as a yellow solid. MS Calcd: 312; MS Found: 313 [M+H] + .

[0590] Step 5: Synthesis of I29:

[0591]

[0592] At 5-10 ° C, NaNO2 (66.2 mg, 0.96 mmol) was added to a solution of compound I30-5a (200 mg, 0.96 mmol) in HOAc / HCl (6 mL / 1 mL). The reaction mixture was stirred at 5-10 ° C for 30 minutes. Then (2-cyanoacetyl) ethyl carbamate (150 mg, 0.96 mmol) was added, followed by a solution of NaOAc (157.44 mg, 1.92 mmol) in H2O (2 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with H2O (20 mL) and extracted with EA (30 mLx2). The combined organic layer was washed with brine (20 mLx2), dried over Na2SO4, filtered and concentrated. The residue was dissolved in 15 mL DMF and KOAc (188.16 mg, 1.92 mmol) was added. The reaction mixture was stirred at 120 ° C for 2 hours. The reaction was diluted with H2O (20 mL) and extracted with EA (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give I29 (14 mg, yield; 5%) as a yellow solid. MS Calcd: 433; MS Found: 434 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ: 8.26 (s, 1H), 7.77 (s, 1H), 7.69 (s, 2H), 7.08 (brs, 1H), 5.31 (s, 2H), 2.92-2.85 (m, 1H), 1.11 (d, J=6.8Hz, 6H).

[0593] Embodiment 31:

[0594] 2-(3,5-dichloro-4-((5-isopropyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I31)

[0595] Step 1: Synthesis of I31-02:

[0596]

[0597] Acetone (50 mL) and Pt / C (5.0 g) were added to a solution of compound I31-01 (10.0 g, 78.06 mmol) in HOAc (100 mL). The reaction mixture was stirred at room temperature under H2 for 2 days. The reaction mixture was detected to be complete by LCMS. The solid was removed by filtration under reduced pressure, and the filtrate was concentrated to give compound I31-02 (15.0 g, crude product) as a gray solid. The crude product can be used in the following reaction without further purification. MS Calcd: 170.2; MS Found: 171.2 [M+H] +.

[0598] Step 2: Synthesis of I31-03:

[0599]

[0600] To a solution of compound I31-02 (1.0 g, 5.88 mmol) in POCl3 (13.7 mL, 147.00 mmol) was added N-Benzyl-N,N,N-triethylammonium chloride (2.7 g, 11.76 mmol). The reaction mixture was heated to 50 ° C and stirred for 7 hours. The reaction was cooled to room temperature and evaporated to dryness in vacuo. At 0 ° C, the residue was carefully quenched with ice water (30 mL) and the slurry was stored in a refrigerator for 7 hours. The resulting white precipitate was collected and thoroughly washed with hexane (30 mLx2) to give compound I31-03 (770.0 mg, crude) as a white solid. The crude product can be used in the following reaction without further purification. MS Calcd: 188.6; MS Found: 189.6 [M + H] +.

[0601] Step 3: Synthesis of I31-04:

[0602]

[0603] Pd / C (500 mg) was added to a solution of compound I31-03 (770.0 mg, 4.09 mmol) in NaOH (100 mL, 2 Naq). The reaction mixture was shaken for 3 hours under a hydrogen atmosphere with an initial pressure of 40 psi. The catalyst was removed by filtration, and the filtrate was acidified to pH = 2 with concentrated HCl. The resulting precipitate was collected, washed and dried to give compound I31-04 (418.0 mg, yield: 66.5%). MS Calcd: 154.2; MS Found: 155.2 [M+H] +.

[0604] Step 4: Synthesis of I31-06:

[0605]

[0606] At 60 ° C, a solution of compound I31-05 (8.2 g, 59.85 mmol), trichloroisocyanuric acid (15.9 g, 65.84 mmol) and concentrated sulfuric acid (50 mL) was stirred for 20 hours. The solution was cooled to 25 ° C and then poured into ice water (100 mL). The resulting mixture was filtered through a diatomaceous earth pad (20 g), and the pad was then washed with ether (50 mL). The organic layer of the filtrate was separated, and the aqueous layer was extracted with ether (30 mL × 2). The collected organic layer was washed with brine (50 mLx2), dried with Na2SO4 and concentrated in vacuo to give a crude product as a light yellow solid. A mixture of the crude product, copper (12.0 g) and chlorobenzene (15 mL) was stirred at 25 ° C for 5 minutes, acetic acid (10 mL) was then added thereto, and the resulting solution was refluxed for 20 hours. After cooling to 25 ° C, the mixture was filtered through a diatomaceous earth pad, and the pad was then washed with toluene (50 mL). The filtrate was washed with brine (20 mL x 3), dried over Na2SO4 and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (PE) to give compound I31-06 (9.0 g, yield: 73.0%) as a yellow solid.

[0607] Step 5: Synthesis of I31-07:

[0608]

[0609] NBS (10.4 g, 58.25 mmol) and BPO (932.0 mg, 0.39 mmol) were added to a solution of compound I31-06 (8.0 g, 38.83 mmol) in CCl4 (50 mL). The reaction mixture was stirred at 90 ° C for 16 hours. The reaction mixture was detected to be complete by TLC (PE). The mixture was poured into 10 mL of water and the product was extracted with EA (100 mL × 3). The organic layer was washed with water (100 mLx2) and 50 mL of brine, and then dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE) to obtain compound I31-07 (9.4 g, yield: 84.9%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ: 8.37 (s, 2H), 4.83 (s, 2H).

[0610] Step 6: Synthesis of I31-08:

[0611]

[0612] Compound I31-04 (390.0 mg, 2.53 mmol) and K2CO3 (1.05 g, 7.60 mmol) were added to a solution of compound I31-07 (722.0 mg, 2.53 mmol) in DMF (20 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was detected to be complete by LCMS. The mixture was poured into 50 mL of water and the product was extracted with EA (50 mL × 3). The organic layer was washed with water (50 mLx2) and 50 mL of brine and then dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (PE: EA = 5: 1) to give compound I31-08 (550.0 mg, yield: 60.6%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ: 11.26 (s, 1H), 8.32 (s, 2H), 7.42 (s, 1H), 5.18 (s, 2H), 2.77-2.68 (m, 1H), 1.08-1.03 (m, 6H). MS Calcd: 358.2; MS Found: 360.2[M+H]+.

[0613] Step 7: Synthesis of I31-09:

[0614]

[0615] Zinc powder (947.0 mg, 14.57 mmol) and NH4Cl (386.0 mg, 7.28 mmol) were added to a solution of compound I31-08 (520.0 mg, 1.46 mmol) in MeOH / H2O (30 / 5 mL). The reaction mixture was stirred at 80 ° C for 3 hours. The reaction mixture was detected to be complete by LCMS. The solid was removed by filtration under reduced pressure, and the filtrate was concentrated to give compound I31-09 (430.0 mg, yield 90.3%) as a yellow solid. The crude product can be used in the following reaction without further purification. MS Calcd: 328.2; MSFound: 330.3 [M + H] + .

[0616] Step 8: Synthesis of I31-11:

[0617]

[0618] At 0 ° C, a solution of compound I31-09 (380.0 mg, 1.16 mmol) in HOAc / HCl (6 / 1 mL) was added with NaNO2 aqueous solution (120.0 mg, 1.74 mmol, 1 mL). The reaction mixture was stirred at 5-10 ° C for 30 minutes. Compound I31-10 (272.0 mg, 1.74 mmol) was then added followed by a solution of NaOAc (286.0 mg, 3.49 mmol, 1 mL) in H2O. The reaction mixture was stirred at 5-10 ° C for 2 hours. The reaction was diluted with H2O (20 mL) and extracted with DCM (30 mLx2). The organic layers were combined and concentrated to give compound I31-11 (320.0 mg, yield: 55.7%) as a yellow solid. The crude product was used in the following reaction without further purification. MS Calcd: 495.3; MS Found: 496.8 [M + H] + .

[0619] Step 9: Synthesis of I31:

[0620]

[0621] KOAc (191.1 mg, 1.95 mmol) was added to a solution of compound I31-11 (320.0 mg, 0.65 mmol) in DMF (15 mL). The reaction mixture was stirred at 120 ° C for 3 hours. The reaction was quenched with water (20 mL). The resulting mixture was extracted with EA (20 mLx3). The combined organic layers were washed with water (20 mL) and 20 mL of brine and then dried over Na2SO4. After filtration, the solvent was removed under reduced pressure. The residue was purified by pre-HPLC to give compound I31 (45.0 mg, yield: 15.4%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ: 7.71 (s, 2H), 7.23 (s, 1H), 7.09 (brs, 2H), 5.11 (s, 2H), 2.74-2.67 (m, 1H), 1.04 (d, J=6.8Hz, 6H). MS Calcd: 449.3; MS Found: 451.0[M+H] + .

[0622] Embodiment 32

[0623] 2-(3,5-dichloro-4-((1-isopropyl-2-oxo-1,2-dihydropyrimidin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I32)

[0624] Step 1: Synthesis of I32-2:

[0625]

[0626] To a solution of compound I32-1 (7 g, 0.04 mol) in ACN (50 mL) was added DBU (7.3 g, 0.048 mol) and 2-iodopropane (8.16 g, 0.048 mol). The mixture was stirred at 70 ° C for 8 hours. The reaction mixture was then diluted with water and extracted with EA (100 mLx5). The combined organic phases were concentrated. The residue was purified by silica gel column chromatography (PE / EA=1 / 10) to give compound I32-2 (4.5 g, yield: 51.8%) as a yellow solid. MS Calcd: 217; MS Found: 218 [M+H] + .

[0627] Step 2: Synthesis of I32-3:

[0628]

[0629] To a solution of compound I32-2 (1.5 g, 6.9 mmol) in DMF (20 mL) was added benzyl alcohol (1.5 g, 13.8 mmol), Cs2CO3 (2.86 g, 20.7 mmol) and KI (0.57 g, 3.5 mmol). The mixture was stirred at 100 ° C for 3 hours. The reaction mixture was diluted with water and extracted with EA (50 mLx2). The combined organic phase was washed with brine (50 mL) and concentrated. The residue was purified by silica gel column chromatography (PE / EA=2 / 1) to give compound I32-3 (0.38 g, yield: 22.5%) as a yellow solid. MS Calcd: 244; MS Found: 245 [M+H] + .

[0630] Step 3: Synthesis of I32-4:

[0631]

[0632] Pd / C (60% wet, 10 wt%, 50 mg) was added to a solution of compound I32-3 (380 mg, 1.56 mmol) in MeOH (10 mL). The mixture was stirred at room temperature under H2 for 2 hours. The reaction was filtered and concentrated to give compound I32-4 (250 mg, yield:> 100%) as a yellow oil. MS Calcd: 154; MS Found: 155 [M+H] + .

[0633] Step 4: Synthesis of I32-5:

[0634]

[0635] Compound I32-A (300 mg, 1.43 mmol) and K2CO3 (591.4 mg, 4.29 mmol) were added to a solution of compound I32-4 (220 mg, 1.43 mmol) in DMF (5 mL). The reaction mixture was stirred at 100 ° C for 1 hour. The reaction mixture was diluted with water and extracted with EA (20 mLx2). The combined organic phase was washed with brine (20 mL) and concentrated. The residue was purified by silica gel column chromatography (PE / EA=2 / 1) to give compound I32-5 (250 mg, yield: 51.0%) as a yellow solid. MSCalcd: 344; MSFound: 345[M+H] + .

[0636] Step 5: Synthesis of I32-6:

[0637]

[0638] To a solution of compound I32-5 (250 mg, 0.73 mmol) in EtOH (10 mL) and water (1 mL) was added Zn (237 mg, 3.64 mmol) and NH4Cl (195 mg, 3.64 mmol). The reaction mixture was stirred at 80 ° C for 5 hours. Then filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH = 20 / 1) to give compound I32-6 (200 mg, yield: 87.7%) as a yellow solid. MS Calcd: 314; MS Found: 315 [M + H] + .

[0639] Step 6: Synthesis of I32:

[0640]

[0641] To a solution of compound I32-6 (200 mg, 0.64 mmol) in HOAc (6 mL) and HCl (1 mL) was added NaNO2 (66.1 mg, 0.96 mmol) at 5-10 ° C. The reaction mixture was stirred at 5-10 ° C for 30 minutes. Then (2-cyanoacetyl) ethyl carbamate (149.5 mg, 0.96 mmol) was added followed by a solution of NaOAc (157.2 mg, 1.92 mmol) in H2O. The reaction mixture was stirred at 5-10 ° C for 5 hours. The reaction was diluted with water and extracted with DCM (20 mL). The combined organic phases were concentrated to give a crude product. The crude product was dissolved in DMF (5 mL) and KOAc (128.6 mg, 1.31 mmol) was added. The mixture was stirred at 120 ° C for 4 hours. Then filtered and concentrated. The residue was purified by prep-HPLC to give I32 (14.5 mg, yield: 7.6%) as a yellow solid. 1 HNMR (400MHz, DMSO-d6) δ: 7.79 (d, J=8Hz, 1H), 7.77 (s, 2H), 5.83 (d, J=8Hz, 1H), 4.72-4.68 (m, 1H), 1.31 (d, J=6.8Hz, 6H), MS Calcd: 434; MS Found: 435[M+H] + .

[0642] Embodiment 33

[0643] 2-(3,5-dichloro-4-((3-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I33)

[0644] Step 1: I33-2:

[0645]

[0646] At 0°C, PMBCl (26 g, 167 mmol) was added to a solution of compound I33-1 (20 g, 141 mmol) and K2CO3 (39 g, 283 mmol) in DMF (100 mL). The resulting mixture was stirred at 70°C overnight, then filtered, washed with DMF and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH=40 / 1) to give compound I33-2 (4.6 g, yield: 12%) as a white solid. MS Calcd: 262; MS Found: 263 [M+H] + .

[0647] Step 2: Synthesis of I33-3:

[0648]

[0649] To a solution of compound I33-2 (4.6 g, 17.56 mmol) in DMF (50 mL) was added 2-iodopropane (7.5 g, 44.12 mmol) and K2CO3 (6 g, 43.48 mmol). The resulting mixture was stirred at 90 ° C overnight, then filtered, washed with DMF and concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH=100 / 1) to give compound I33-3 (300 mg, yield: 12%) as a white solid. MS Calcd: 304; MS Found: 305 [M+H] + .

[0650] Step 3: I33-4:

[0651]

[0652] To a solution of compound I33-3 (4.2 g, 13.81 mmol) in DCM (50 mL) was added TFA (20 mL) and TfOH (2 mL) at 0°C. The resulting mixture was stirred at room temperature for 4 hours. It was then concentrated and the pH was adjusted to 8 with Na2CO3 and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH=60 / 1) to give compound I33-4 (2 g, yield: 79%) as a white solid. MS Calcd: 184; MS Found: 185 [M+H] + .

[0653] Step 4: Synthesis of I33-5:

[0654]

[0655] At 0°C, BBr3 (17.6 g, 17.70 mmol) was added dropwise to a solution of compound I33-4 (2.6 g, 14.13 mmol) in DCM (8 mL), and stirred at room temperature. The pH of the reaction mixture was adjusted to 8 with Na2CO3 and concentrated. The product was dissolved in THF, filtered and concentrated to give compound I33-5 (2 g, yield: 83%) as a white solid. MS Calcd: 170; MS Found: 171 [M+H] + .

[0656] Step 5: Synthesis of I33-6:

[0657]

[0658] 1,3-dichloro-2-fluoro-5-nitrobenzene (2 mg, 9.52 mmol) and K2CO3 (2.6 mg, 18.84 mmol) were added to a solution of compound I33-5 (1.6 mg, 9.41 mmol) in DMF (20 mL). The resulting mixture was stirred at 50 ° C for 2 hours. The reaction was diluted with H2O (20 mL) and extracted with EA (30 mLx2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (DCM / MeOH=60 / 1) to give compound I33-6 (1.5 g, yield: 44%) as a white solid. MS Calcd: 359; MS Found: 360 [M+H] + .

[0659] Step 6: Synthesis of I33-7:

[0660]

[0661] To a solution of compound I33-6 (1.1 mg, 3.06 mmol) in MeOH (10 mL) and water (1 mL) was added Zn (2 g, 30.70 mmol) and NH4Cl (1.6 g, 30.19 mmol). The reaction mixture was stirred at 80 ° C for 3 hours, then filtered and concentrated. The residue was purified by silica gel flash chromatography (DCM / MeOH = 30 / 1) to give compound I33-7 (0.9 g, yield: 90%) as a white solid. MS Calcd: 329; MS Found: 330 [M + H] + .

[0662] Step 7: Synthesis of I33-8:

[0663]

[0664] At 5-10 ° C, NaNO2 (157 mg, 2.28 mmol) was added to a solution of compound I33-7 (500 mg, 1.52 mmol) in HOAc / HCl=12 mL / 2 mL. The reaction mixture was stirred at 5-10 ° C for 30 minutes. Then 2-cyanoacetyl) ethyl carbamate (356 mg, 2.28 mmol) was added followed by a solution of NaOAc (374 mg, 4.56 mmol) in H2O. The reaction mixture was stirred at 5-10 ° C for 8 hours. The reaction was diluted with H2O (20 mL) and extracted with DCM (30 mLx2). The combined organic layers were concentrated to give compound I33-8 (700 mg, yield: 93%) as a yellow solid. MS Calcd: 496; MS Found: 497 [M+H] + .

[0665] Step 8: Synthesis of I33:

[0666]

[0667] To a solution of compound I33-8 (700 mg, 1.41 mmol) in DMF (15 mL) was added KOAc (415 mg, 4.23 mmol). The reaction mixture was stirred at 120 ° C for 3 hours. Then filtered and concentrated. The residue was purified by prep-HPLC to give I33 (75.6 mg, yield: 12%) as a white solid. 1 HNMR (400MHz, DMSO-d6) δ: 13.24 (s, 1H), 10.98 (d, J=6.0Hz, 1H), 7.67 (s, 2H), 7.39 (d, J=6.4Hz, 1H), 5.00-4.97 (m, 1H), 1.37 (d, J=7.2Hz, 6H). MS Calcd: 450; MS Found: 451[M+H] + .

[0668] Embodiment 34

[0669] 2-(3,5-dichloro-4-((1-(hydroxymethyl)-5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I34)

[0670] Embodiment 35

[0671] 2-(3,5-dibromo-4-((5-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I35)

[0672] Embodiment 36

[0673] 2-(3,5-dichloro-4-((5-cyclobutyl-6-oxo-1,6-dihydropyridin-3-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I36)

[0674] Embodiment 37

[0675] 2-(3,5-dichloro-4-((3-isopropyl-1H-indol-5-yl)oxy)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I37)

[0676] Embodiment 38

[0677] 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl)phenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile (I38)

[0678] Embodiment 39

[0679] The biological properties of the examples were investigated based on the following assays.

[0680] Thyroid hormone receptor binding in vitro assay

[0681] The interaction between the compounds of the invention and the human thyroid receptor (TR) was evaluated by a time-resolved fluorescence resonance energy transfer (TR-FRET) competition assay. FRET describes the radiationless energy transfer between two chromophores: a donor fluorophore in an excited state can transfer energy to a neighboring acceptor fluorophore (usually <10 nm). Compared to standard FRET, TR-FRET combines the principles of time-resolved fluorescence (TRF) and FRET. TRF uses long-lived lanthanide chelates as donors, and lanthanide chelates are unique in that their excited state lifetimes can reach milliseconds or longer. Suitable neighborhoods for FRET are known and available in the art. The experiment used LanthaScreen from Invitrogen TM TR-FRETThyroid Receptor beta Coactivator Assay Kit.

[0682] The test was performed as follows: First, a reaction buffer containing 50 mM Tris-HCl (pH 7.4) and 100 mM NaCl, 1 mM EDTA, 50 mM KF, 1 mM DTT, 1 mM MgCl2, 10% glycerol, 0.01% NP-40, and 0.1% BSA was prepared; then, the test and control dilutions were prepared using the buffer; 3,3',5-triiodothyronine (T3) was used as a positive control agonist. Third, 5 μl of 4x dilution and 5 μl of TRαLBD (4x, 4 nM) (or 5 μl of TRβLBD, 4x, 2 nM) were added to a 384-well plate (784075, Greiner). Then, 10 μl of a solution consisting of 400 nM biotin-SRC2-2 (2x) and anti-GST Eu (1:200, 2x) and 50 nM anti-biotin-d2 (2x) in 1x reaction buffer was added to start the reaction. The culture plate was centrifuged at 1000 g for 1 minute and then incubated at room temperature for 1 hour in the dark; finally, the plate was read using an Envision 2104 plate reader at wavelengths of 665 nm and 615 nm.

[0683] Calculate the ratio of each well (ratio 665nm / 615nm -ratio 背景 ). Calculate the activity percentage and EC 50 The effect-dose curve was plotted. The relative selectivity was calculated as EC 50 TRα / EC 50 The ratio of TRβ.

[0684] Test results:

[0685]

[0686]

[0687] In vitro assay for thyroid hormone transcriptional activity

[0688] The TRα-LBD (or TRβ-LBD) and RXRα-LBD coding sequences were inserted into the pBIND expression vector (Promega, E1581) to express TRα-GAL4 (or TRβ-GAL4) and RXRα-GAL4 chimeric receptors, respectively. The two expression vectors and the reporter vector (pGL4.35, which carries the luciferase reporter gene driven by the GAL4 promoter) were co-transfected into HEK293T host cells. After the agonist binds to the corresponding TRα-GAL4 (or TRβ-GAL4) chimeric receptor, the chimeric receptor binds to the GAL4 binding site and promotes the transcription of the reporter gene. The ability of the test compound to promote the transcriptional activity of TRα (or TRβ) was determined respectively.

[0689] The experiment was carried out as follows: first, the stock solution of the compound was serially diluted with DMSO; then, 2.5x10 6 HEK293T cells were seeded into 60 mm culture dishes and cultured at 37°C, 5% CO2 for 16 h. In the third step, DNA and LipoLTX reagents as well as 2.5 μg TRβ (or 2.5 μg TRα) plasmid / 2.5 μg RXRα plasmid / 1 μg pGL4.35 luciferase plasmid were added to Opti-MEM TM The transfected cells were mixed in the culture medium and incubated at 37°C, 5% CO2 for 4-7 hours. In the fourth step, the cells were seeded at 17,000 cells / well and the diluted compound solution was added. The cells were cultured at 37°C, 5% CO2 for 16-20 hours; finally, 25 μl of luciferase detection reagent (LDT) was added to the detection plate at room temperature; shake at room temperature for at least 5 minutes, and then the luminescence value was read with the Evision2104 plate reader. EC was calculated by simulating the % inhibition value and the logarithm of the compound concentration by nonlinear regression (dose response-variable slope) in Graphpad5.0 50 In the test of the present invention, the Z'-factor was > 0.5.

[0690] Test results:

[0691]

[0692] It should be understood that the present invention is not limited to the specific embodiments of the invention described above, as variations may be made and still fall within the scope of the appended claims.

Claims

1. A compound of formula (I) or (Ia), or a tautomer or a pharmaceutically acceptable salt thereof, in: A is O or CH2; B is N or CH; X is O or NR 1 or CHR 1 ; R 1 is selected from a bond, H, methyl, ethyl, propyl, butyl, pentyl or hexyl; R 2 is H, methyl, ethyl, propyl, butyl, pentyl or hexyl; or R 1 and R 2 Together with the X-C=C to which they are attached, they form a 5- to 9-membered carbocyclic or heterocyclic ring which is unsubstituted or replaced by R 6 and R 7 Replacement, R 6 and R 7 independently selected from H, methyl, ethyl, propyl, butyl, pentyl or hexyl; R 3 and R 4 Independently selected from H, F, Cl, Br and CH3; R 5 Selected from:

2. The compound according to claim 1, wherein B is CH.

3. The compound according to claim 1, wherein A is O and B is CH.

4. The compound according to claim 3, wherein R 5 yes 5. The compound according to claim 4, wherein X is NR 1 or CHR 1 , R 1 and R 2 Together with the X-C=C to which they are attached, they form a 5-membered heterocyclic ring which is: R 6 and R 7 Independently selected from H or Me.

6. The compound according to claim 4, wherein the compound is selected from the group consisting of:

7. A compound, or a tautomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 and a pharmaceutically acceptable carrier and / or adjuvant.

9. Use of a compound according to any one of claims 1 to 7 for the preparation of a medicament for the therapeutic and / or prophylactic treatment of diseases modulated by thyroid hormone analogues.

10. Use of a compound according to any one of claims 1 to 7 in the preparation of a medicament for the treatment and / or preventive treatment of metabolic diseases, obesity, hyperlipidemia, hypercholesterolemia, diabetes, non-alcoholic steatohepatitis, atherosclerosis, cardiovascular disease, hypothyroidism, thyroid cancer and related conditions and diseases.

Images