Patent Grant
9567326
The present invention concerns compounds, compositions and methods for the treatment of cancer.
Acute Lymphoblastic Leukemia (ALL) is the most common malignancy in children and common varieties are cured by chemotherapy in 75%-85% of the cases. Collectively the less common T cell and rare B cell subsets represent less than 2000 cases yearly and thus can be classified as a rare disease; these subsets have a poorer prognosis. Unfortunately with either subset, resistance to and relapse from therapy is a major cause of pediatric cancer death. In addition, ALL chemotherapies can cause late complications that are increasingly recognized in pediatric survivor populations. In fact, in pediatric cancer survivors, the incidence of severe late effects (neurocognitive sequelae, auditory complications, cardiovascular dysfunction, gastrointestinal/hepatic dysfunction, growth delay, secondary malignancies, and infertility) directly related to therapy is approximately 25%. A better understanding of therapeutic resistance and its reversal could not only help those who relapse but may help lower the dose of chemotherapy needed in ALL patients thus reducing long-term toxicity for future survivors.
A first aspect of the invention is active compounds of Formula I or II:
wherein:
ring A is a 5- or 6-membered heteroaryl group (for example, pyridyl, pyrimidyl, thiazol, furanyl, pyridazinyl, pyrazinyl, imidazol, etc.). The dashed lines are optional double bonds. X is N or O. Y is a carbon atom or an S or N heteroatom in ring A in any suitable location.
R1 is —R5R6, where R5 is a covalent bond, C1 to C3 alkyl or a linker group (for example, sulfonamide, ether, ester, amine, amide, etc.) and R6 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl or alkyl, and wherein R6 is optionally substituted one, two or three times with independently selected polar groups;
R2 is —R7R8, where R7 is a covalent bond or C1 to C3 alkyl and R8 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl, and wherein R8 is optionally substituted one, two or three times with independently selected polar groups;
R3 is selected from the group consisting of H, alkyl, aryl, arylalkyl; cycloalkylalkyl, heterocycloalkylalkyl, heteroaryalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times with independently selected polar groups;
R4 is H, loweralkyl, halo, or loweralkoxy;
or a pharmaceutically acceptable salt thereof.
A further aspect of the invention is an active compound as described herein in a pharmaceutically acceptable carrier.
A further aspect of the invention is a method of treating cancer in a subject in need thereof, comprising administering said subject an active compound as described herein in an amount effective to treat the cancer.
A further aspect of the invention is an active compound as described herein for use in treating cancer, and/or for the preparation of a medicament for the treatment of cancer.
“Alkyl” as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like. “Lower alkyl” as used herein, is a subset of alkyl, in some embodiments preferred, and refers to a straight or branched chain hydrocarbon group containing from 1 to 4 carbon atoms. Representative examples of lower alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, and the like. The term “alkyl” or “loweralkyl” is intended to include both substituted and unsubstituted alkyl or loweralkyl unless otherwise indicated and these groups may be substituted with groups selected from halo (e.g., haloalkyl), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy (thereby creating a polyalkoxy such as polyethylene glycol), alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, acyloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O)m, haloalkyl-S(O)m, alkenyl-S(O)m, alkynyl-S(O)m, cycloalkyl-S(O)m, cycloalkylalkyl-S(O)m, aryl-S(O)m, arylalkyl-S(O)m, heterocyclo-S(O)m, heterocycloalkyl-S(O)m, amino, carboxy, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m=0, 1, 2 or 3.
“Alkenyl” as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkenyl 1 to 4 carbon atoms) which include 1 to 4 double bonds in the normal chain. Representative examples of alkenyl include, but are not limited to, vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2,4-heptadiene, and the like. The term “alkenyl” or “loweralkenyl” is intended to include both substituted and unsubstituted alkenyl or loweralkenyl unless otherwise indicated and these groups may be substituted with groups as described in connection with alkyl and loweralkyl above.
“Alkynyl” as used herein alone or as part of another group, refers to a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms (or in loweralkynyl 1 to 4 carbon atoms) which include 1 triple bond in the normal chain. Representative examples of alkynyl include, but are not limited to, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, and the like. The term “alkynyl” or “loweralkynyl” is intended to include both substituted and unsubstituted alkynyl or loweralkynyl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.
“Cycloalkyl” as used herein alone or as part of another group, refers to a saturated or partially unsaturated cyclic hydrocarbon group containing from 3, 4 or 5 to 6, 7 or 8 carbons (which carbons may be replaced in a heterocyclic group as discussed below). Representative examples of cycloalkyl include, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. These rings may be optionally substituted with additional substituents as described herein such as halo or loweralkyl. The term “cycloalkyl” is generic and intended to include heterocyclic groups as discussed below unless specified otherwise.
“Heterocyclic group” or “heterocyclo” as used herein alone or as part of another group, refers to an aliphatic (e.g., fully or partially saturated heterocyclo) or aromatic (e.g., heteroaryl) monocyclic-or a bicyclic-ring system. Monocyclic ring systems are exemplified by any 5 or 6 membered ring containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, nitrogen and sulfur. The 5 membered ring has from 0-2 double bonds and the 6 membered ring has from 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithiane, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazoline, thiazolidine, thiophene, thiomorpholine, thiomorpholine sulfone, thiopyran, triazine, triazole, trithiane, and the like. Bicyclic ring systems are exemplified by any of the above monocyclic ring systems fused to an aryl group as defined herein, a cycloalkyl group as defined herein, or another monocyclic ring system as defined herein. Representative examples of bicyclic ring systems include but are not limited to, for example, benzimidazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxadiazole, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, indazole, indole, indoline, indolizine, naphthyridine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, purine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline, thiopyranopyridine, and the like. These rings include quaternized derivatives thereof and may be optionally substituted with groups selected from halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl, hydroxyl, alkoxy, alkenyloxy, alkynyloxy, haloalkoxy, cycloalkoxy, cycloalkylalkyloxy, aryloxy, arylalkyloxy, heterocyclooxy, heterocyclolalkyloxy, mercapto, alkyl-S(O)m, haloalkyl-S(O)m, alkenyl-S(O)m, alkynyl-S(O)m, cycloalkyl-S(O)m, cycloalkylalkyl-S(O)m, aryl-S(O)m, arylalkyl-S(O)m, heterocyclo-S(O)m, heterocycloalkyl-S(O)m, amino, alkylamino, alkenylamino, alkynylamino, haloalkylamino, cycloalkylamino, cycloalkylalkylamino, arylamino, arylalkylamino, heterocycloamino, heterocycloalkylamino, disubstituted-amino, acylamino, acyloxy, ester, amide, sulfonamide, urea, alkoxyacylamino, aminoacyloxy, nitro or cyano where m=0, 1, 2 or 3.
“Aryl” as used herein alone or as part of another group, refers to a monocyclic carbocyclic ring system or a bicyclic carbocyclic fused ring system having one or more aromatic rings. Representative examples of aryl include, azulenyl, indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl, and the like. The term “aryl” is intended to include both substituted and unsubstituted aryl unless otherwise indicated and these groups may be substituted with the same groups as set forth in connection with alkyl and loweralkyl above.
“Arylalkyl” as used herein alone or as part of another group, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-naphth-2-ylethyl, and the like.
“Heteroaryl” as used herein is as described in connection with heterocyclo above.
“Alkoxy” as used herein alone or as part of another group, refers to an alkyl or loweralkyl group, as defined herein (and thus including substituted versions such as polyalkoxy), appended to the parent molecular moiety through an oxy group, —O—. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like.
“Halo” as used herein refers to any suitable halogen, including —F, —Cl, —Br, and —I.
“Mercapto” as used herein refers to an —SH group.
“Azido” as used herein refers to an —N3 group.
“Cyano” as used herein refers to a —CN group.
“Formyl” as used herein refers to a —C(O)H group.
“Carboxylic acid” as used herein refers to a —C(O)OH group.
“Hydroxyl” as used herein refers to an —OH group.
“Nitro” as used herein refers to an —NO2 group.
“Acyl” as used herein alone or as part of another group refers to a —C(O)R radical, where R is any suitable substituent such as aryl, alkyl, alkenyl, alkynyl, cycloalkyl or other suitable substituent as described herein.
“Alkylthio” as used herein alone or as part of another group, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through a thio moiety, as defined herein. Representative examples of alkylthio include, but are not limited, methylthio, ethylthio, tert-butylthio, hexylthio, and the like.
“Amino” as used herein means the radical —NH2.
“Alkylamino” as used herein alone or as part of another group means the radical —NHR, where R is an alkyl group.
“Arylalkylamino” as used herein alone or as part of another group means the radical —NHR, where R is an arylalkyl group.
“Disubstituted-amino” as used herein alone or as part of another group means the radical —NRaRb, where Ra and Rb are independently selected from the groups alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.
“Acylamino” as used herein alone or as part of another group means the radical —NRaRb, where Ra is an acyl group as defined herein and Rb is selected from the groups hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclo, heterocycloalkyl.
“Acyloxy” as used herein alone or as part of another group means the radical —OR, where R is an acyl group as defined herein.
“Ester” as used herein alone or as part of another group refers to a —C(O)OR radical, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Amide” as used herein alone or as part of another group refers to a —C(O)NRaRb radical, where Ra and Rb are any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Sulfoxyl” as used herein refers to a compound of the formula —S(O)R, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Sulfonyl” as used herein refers to a compound of the formula —S(O)(O)R, where R is any suitable substituent such as amino, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Sulfonate” as used herein refers to a compound of the formula —S(O)(O)OR, where R is any suitable substituent such as alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Sulfonic acid” as used herein refers to a compound of the formula —S(O)(O)OH.
“Sulfonamide” as used herein alone or as part of another group refers to a —S(O)2NRaRb radical, where Ra and Rb are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Urea” as used herein alone or as part of another group refers to an —N(Rc)C(O)NRaRb radical, where Ra, Rb and Re are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Alkoxyacylamino” as used herein alone or as part of another group refers to an —N(Ra)C(O)ORb radical, where Ra, Rb are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Aminoacyloxy” as used herein alone or as part of another group refers to an —OC(O)NRaRb radical, where Ra and Rb are any suitable substituent such as H, alkyl, cycloalkyl, alkenyl, alkynyl or aryl.
“Polar group” as used herein refers to a group wherein the nuclei of the atoms covalently bound to each other to form the group do not share the electrons of the covalent bond(s) joining them equally; that is the electron cloud is denser about one atom than another. This results in one end of the covalent bond(s) being relatively negative and the other end relatively positive; i.e., there is a negative pole and a positive pole. Examples of polar groups include, without limitations, halo, hydroxy, alkoxy, carboxy, nitro, cyano, amino (primary, secondary and tertiary), amido, ureido, sulfonamido, sulfinyl, sulfhydryl, silyl, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido, N-amido, sulfonyl, N-tert-butoxycarbonyl (or “t-BOC”) groups, phosphono, morpholino, piperazinyl, tetrazolo, and the like. See, e.g., U.S. Pat. No. 6,878,733, as well as alcohol, thiol, polyethylene glycol, polyol (including sugar, aminosugar, uronic acid), sulfonamide, carboxamide, hydrazide, N-hydroxycarboxamide, urea, metal chelates (including macrocyclic ligand or crown ether metal chelates). The polar group can be an ionic group.
“Ionic group” as used herein includes anionic and cationic groups, and includes groups (sometimes referred to as “ionogenic” groups) that are uncharged in one form but can be easily converted to ionic groups (for example, by protonation or deprotonation in aqueous solution). Examples include but are not limited to carboxylate, sulfonate, phosphate, amine, N-oxide, and ammonium (including quaternized heterocyclic amines such as imidazolium and pyridinium) groups. See, e.g., U.S. Pat. Nos. 6,478,863; 6,800,276; and 6,896,246. Additional examples include uronic acids, carboxylic acid, sulfonic acid, amine, and moieties such as guanidinium, phosphoric acid, phosphonic acid, phosphatidyl choline, phosphonium, borate, sulfate, etc.
“Deuterium” as used herein alone or as part of another group, refers to a safe, non-radioactive relative of hydrogen. Any hydrogen in a group or substituent described above may be replaced with deuterium to provide a “deuterated” compound, in some embodiments to modify and/or improve metabolic stability, resulting in better safety, tolerability and/or efficacy.
“Linker group” or “linking group” as used herein are generally bivalent aromatic, aliphatic, or mixed aromatic and aliphatic groups. Thus linking groups include linear or branched, substituted or unsubstituted aryl, alkyl, alkylaryl, or alkylarylalkyl linking groups, where the alkyl groups are saturated or unsaturated, and where the alkyl and aryl groups optionally containing independently selected heteroatoms such as 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, shorter linking groups containing from 2 to 5, 10, or 20 carbon atoms are preferred, along with any heteroatoms as described above. Numerous examples of suitable linking groups are known, including but not limited to those described in, U.S. Pat. Nos. 8,247,572; 8,097,609; 6,624,317; 6,613,345; 6,596,935; and 6,420,377, the disclosures of which are incorporated by reference herein in their entirety.
“Treat” as used herein refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in one or more symptoms), delay in the progression of the disease, delay in onset of the disease, etc.
“Pharmaceutically acceptable” as used herein means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
Active compounds of the present invention may optionally be administered in conjunction with other compounds useful in the treatment of cancer. The other compounds may optionally be administered concurrently. As used herein, the word “concurrently” means sufficiently close in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occurring within a short time period before or after each other).
The present invention is primarily concerned with the treatment of human subjects, but the invention may also be carried out on animal subjects, particularly mammalian subjects such as mice, rats, dogs, cats, livestock and horses for veterinary purposes, and for drug screening and drug development purposes. Subjects may be of any age, including infant, juvenile, adolescent, adult, and geriatric subjects.
1. Active Compounds.
As noted above, the present invention provides active compounds of Formula I or II:
wherein:
ring A is a 5- or 6-membered heteroaryl group (for example, pyridyl, pyrimidyl, thiazol, furanyl, pyridazinyl, pyrazinyl, imidazol, etc.). The dashed lines are optional double bonds. X is N or O. Y is a carbon atom or an S or N heteroatom in ring A in any suitable location.
R1 is —R5R6, where R5 is a covalent bond, C1 to C3 alkyl or a linker group (for example, sulfonamide, ether, ester, amine, amide, etc.) and R6 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocycloalkyl, alkylaryl, alkylheteroaryl or alkyl, and wherein R6 is optionally substituted one, two or three times with independently selected polar groups;
R2 is —R7R8, where R7 is a covalent bond or C1 to C3 alkyl and R8 is cycloalkyl, heterocycloalkyl, aryl, heteroaryl or alkyl, and wherein R8 is optionally substituted one, two or three times with independently selected polar groups;
R3 is selected from the group consisting of H, alkyl, aryl, arylalkyl; cycloalkylalkyl, heterocycloalkylalkyl, heteroaryalkyl, and alkoxyalkyl, each of which is optionally substituted one, two or three times with independently selected polar groups;
R4 is H, loweralkyl, halo, or loweralkoxy;
or a pharmaceutically acceptable salt thereof.
In some embodiments of the foregoing, R5 is a covalent bond; in other embodiments, R5 is C1 to C3 alkylene such as —CH2— or R5 is a linker group (for example, sulfonamide, amide, etc.)
In some embodiments of the foregoing, R7 is a covalent bond; in other embodiments, R7 is C1 to C3 alkylene such as —CH2—.
In some embodiments, R6 is phenyl, piperidyl, or C1-C8 alkyl, or C3 to C8 cycloalkyl, which phenyl, pipyridyl, alkyl, or cycloalkyl alkyl is unsubstituted or substituted from 1 to 3 times with sulfono, halo, amino, nitro, alkyl, alkoxyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.
In some embodiments, wherein R8 is C1-C8 alkyl or cyclohexyl, which alkyl or cyclohexyl is unsubstituted or substituted from 1 to 3 times with hydroxyl or amino.
In some embodiments, R3 is C1-C8 alkyl, C3-C8 cycloalkyl, C4-C12 cycloalkylalkyl, C3-C8 heterocycloalkyl, C4-C12 heterocycloalkylalkyl, C4-C12 arylalkyl, C4-C12 heteroarylalkyl, each of which is unsubstituted or substituted from one to three times with hydroxyl, halo, or alkoxy.
In some embodiments, R4 is H.
Particular examples of the foregoing include, but are not limited to:
including pharmaceutically acceptable salts thereof.
More particular examples of compounds of the present invention include but are not limited to those set forth in Tables 1-8 below.
The active compounds disclosed herein can, as noted above, be provided in the form of their pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; (b) salts formed from elemental anions such as chlorine, bromine, and iodine, and (c) salts derived from bases, such as ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium, and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine.
Active compounds as described herein can be prepared in accordance with known procedures, or variations thereof that will be apparent to those skilled in the art.
2. Pharmaceutical Formulations.
The active compounds described above may be formulated for administration in a pharmaceutical carrier in accordance with known techniques. See, e.g., Remington, The Science And Practice of Pharmacy (9th Ed. 1995). In the manufacture of a pharmaceutical formulation according to the invention, the active compound (including the physiologically acceptable salts thereof) is typically admixed with, inter alia, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient. The carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01 or 0.5% to 95% or 99% by weight of the active compound. One or more active compounds may be incorporated in the formulations of the invention, which may be prepared by any of the well known techniques of pharmacy comprising admixing the components, optionally including one or more accessory ingredients.
The formulations of the invention include those suitable for oral, rectal, topical, buccal (e.g., sub-lingual), vaginal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous), topical (i.e., both skin and mucosal surfaces, including airway surfaces), transdermal administration, and intraventricular injection (injection into a ventricle of the brain, e.g., by an implanted catheter or omman reservoir, such as in the case of morbid obesity) and although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the particular active compound which is being used.
Formulations suitable for oral administration may be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Such formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above). In general, the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing, in a suitable machine, the compound in a free-flowing form, such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, and/or surface active/dispersing agent(s). Molded tablets may be made by molding, in a suitable machine, the powdered compound moistened with an inert liquid binder.
Formulations suitable for buccal (sub-lingual) administration include lozenges comprising the active compound in a flavoured base, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.
Formulations of the present invention suitable for parenteral administration comprise sterile aqueous and non-aqueous injection solutions of the active compound, which preparations are preferably isotonic with the blood of the intended recipient. These preparations may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The formulations may be presented in unit\dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or water-for-injection immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. For example, in one aspect of the present invention, there is provided an injectable, stable, sterile composition comprising a compound of Formula (I), or a salt thereof, in a unit dosage form in a sealed container. The compound or salt is provided in the form of a lyophilizate which is capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid composition suitable for injection thereof into a subject. The unit dosage form typically comprises from about 10 mg to about 10 grams of the compound or salt. When the compound or salt is substantially water-insoluble, a sufficient amount of emulsifying agent which is physiologically acceptable may be employed in sufficient quantity to emulsify the compound or salt in an aqueous carrier. One such useful emulsifying agent is phosphatidyl choline.
Formulations suitable for rectal administration are preferably presented as unit dose suppositories. These may be prepared by admixing the active compound with one or more conventional solid carriers, for example, cocoa butter, and then shaping the resulting mixture.
Formulations suitable for topical application to the skin preferably take the form of an ointment, cream, lotion, paste, gel, spray, aerosol, or oil. Carriers which may be used include petroleum jelly, lanoline, polyethylene glycols, alcohols, transdermal enhancers, and combinations of two or more thereof.
Formulations suitable for transdermal administration may be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, for example, Pharmaceutical Research 3 (6):318 (1986)) and typically take the form of an optionally buffered aqueous solution of the active compound. Suitable formulations comprise citrate or bis\tris buffer (pH 6) or ethanol/water and contain from 0.1 to 0.2M active ingredient.
Further, the present invention provides liposomal formulations of the compounds disclosed herein and salts thereof. The technology for forming liposomal suspensions is well known in the art. When the compound or salt thereof is an aqueous-soluble salt, using conventional liposome technology, the same may be incorporated into lipid vesicles. In such an instance, due to the water solubility of the compound or salt, the compound or salt will be substantially entrained within the hydrophilic center or core of the liposomes. The lipid layer employed may be of any conventional composition and may either contain cholesterol or may be cholesterol-free. When the compound or salt of interest is water-insoluble, again employing conventional liposome formation technology, the salt may be substantially entrained within the hydrophobic lipid bilayer which forms the structure of the liposome. In either instance, the liposomes which are produced may be reduced in size, as through the use of standard sonication and homogenization techniques.
Of course, the liposomal formulations containing the compounds disclosed herein or salts thereof, may be lyophilized to produce a lyophilizate which may be reconstituted with a pharmaceutically acceptable carrier, such as water, to regenerate a liposomal suspension.
Other pharmaceutical compositions may be prepared from the water-insoluble compounds disclosed herein, or salts thereof, such as aqueous base emulsions. In such an instance, the composition will contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the desired amount of the compound or salt thereof. Particularly useful emulsifying agents include phosphatidyl cholines, and lecithin.
In addition to compounds of formula (I) or their salts, the pharmaceutical compositions may contain other additives, such as pH-adjusting additives. In particular, useful pH-adjusting agents include acids, such as hydrochloric acid, bases or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Further, the compositions may contain microbial preservatives. Useful microbial preservatives include methylparaben, propylparaben, and benzyl alcohol. The microbial preservative is typically employed when the formulation is placed in a vial designed for multidose use. Of course, as indicated, the pharmaceutical compositions of the present invention may be lyophilized using techniques well known in the art.
3. Dosage and Routes of Administration.
As noted above, the present invention provides pharmaceutical formulations comprising the active compounds (including the pharmaceutically acceptable salts thereof), in pharmaceutically acceptable carriers for oral, rectal, topical, buccal, parenteral, intramuscular, intradermal, or intravenous, and transdermal administration.
The therapeutically effective dosage of any specific compound, the use of which is in the scope of present invention, will vary somewhat from compound to compound, and patient to patient, and will depend upon the condition of the patient and the route of delivery. As a general proposition, a dosage from about 0.1 to about 50 mg/kg will have therapeutic efficacy, with all weights being calculated based upon the weight of the active compound, including the cases where a salt is employed. Toxicity concerns at the higher level may restrict intravenous dosages to a lower level such as up to about 10 mg/kg, with all weights being calculated based upon the weight of the active base, including the cases where a salt is employed. A dosage from about 10 mg/kg to about 50 mg/kg may be employed for oral administration. In some embodiments, a dosage from about 0.5 mg/kg to 5 mg/kg may be employed for intramuscular injection. In some embodiments, dosages are 1 μmmol/kg to 50 μmol/kg, and more preferably 22 μmol/kg and 33 μmol/kg of the compound for intravenous or oral administration. The duration of the treatment can be once per day for a period of two to three weeks or until the condition is essentially controlled.
Active compounds may be administered as pharmaceutically acceptable prodrugs, which are those prodrugs of the active compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, commensurate with a reasonable risk/benefit ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term “prodrug” refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel delivery Systems, Vol. 14 of the A.C.S. Symposium Series and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference herein. See also U.S. Pat. No. 6,680,299 Examples include a prodrug that is metabolized in vivo by a subject to an active drug having an activity of active compounds as described herein, wherein the prodrug is an ester of an alcohol or carboxylic acid group, if such a group is present in the compound; an acetal or ketal of an alcohol group, if such a group is present in the compound; an N-Mannich base or an imine of an amine group, if such a group is present in the compound; or a Schiff base, oxime, acetal, enol ester, oxazolidine, or thiazolidine of a carbonyl group, if such a group is present in the compound, such as described in U.S. Pat. No. 6,680,324 and U.S. Pat. No. 6,680,322.
As noted above, the active compounds described herein are useful for the treatment of cancer. Example cancers that may be treated by the compounds and methods of the invention include, but are not limited to, myeloid leukemia, lymphoblastic leukemia, melanoma, breast, lung, colon, liver, gastric, kidney, ovarian, uterine, and brain cancer.
The present invention is explained in greater detail in the following non-limiting Examples.
A solution of 2,4-dichloropyrimidine-5-carbonyl chloride (422 mg, 2.0 mmol) in dichloromethane (10 mL) was added 4-(morpholinosulfonyl)aniline (508 mg, 2.1 mmol) and DIEA (387 mg, 3.0 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. Then, water was added. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to give the title compound as a white solid (701.2 mg, 84%). 1H NMR (400 MHz, DMSO-d6) δ 11.98-11.90 (m, 1H), 8.29 (d, J=6.4 Hz, 1H), 7.89 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.8 Hz, 2H), 3.65-3.56 (m, 4H), 2.87-2.78 (m, 4H); MS m/z 418.30 [M+H]+.
A solution of 2,4-dichloro-N-(4-(morpholinosulfonyl)phenyl)pyrimidine-5-carboxamide (700 mg, 1.68 mmol) in IPA (15 mL) was added trans-4-aminocyclohexanol (231.4 mg, 2.2 mmol) and DIEA (387 mg, 3.0 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 50 min and warmed to room temperature and stirred for another 50 min. Then the solvent was removed, the residue was dissolved in a mixture of DCM and methanol (20 mL, 3:2, v/v), the suspension was filtered though a filter paper to give the title compound as a white solid (683.4 mg, 82%). 1H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 8.69 (s, 1H), 7.96-7.89 (m, 2H), 7.76-7.70 (m, 2H), 4.57 (s, 1H), 3.93-3.81 (m, 1H), 3.64-3.57 (m, 4H), 3.49-3.40 (m, 1H), 2.88-2.78 (m, 4H), 1.95-1.86 (m, 2H), 1.85-1.76 (m, 2H), 1.38-1.20 (m, 4H); MS m/z 496.20 [M+H]+.
A solution of 2-chloro-4-(((1r,4r)-4-hydroxycyclohexyl)amino)-N-(4-(morpholinosulfonyl)phenyl)pyrimidine-5-carboxamide (86 mg, 0.17 mmol) in IPA (10 mL) was added butylamine (59.6 mg, 0.81 mmol) and DIEA (124.7 mg, 0.96 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature. Water was then added. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to give the title compound as a white solid (59.3 mg, 64%). 1H NMR (400 MHz, CD3OD+CDCl3) δ 8.21 (s, 1H), 7.71-7.64 (m, 2H), 7.59-7.53 (m, 2H), 3.93-3.77 (m, 1H), 3.74-3.64 (m, 4H), 3.63-3.58 (m, 4H), 3.56-3.46 (m, 1H), 3.26 (t, J=7.1 Hz, 2H), 2.91-2.81 (m, 4H), 2.05-1.95 (m, 2H), 1.93-1.82 (m, 2H), 1.50-1.41 (m, 2H), 1.33-1.17 (m, 6H), 0.83 (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CD3OD+CDCl3) δ 166.8, 156.4, 143.5, 128.8, 128.6, 120.3, 120.2, 69.2, 66.0, 45.9, 41.0, 33.4, 31.6, 30.2, 20.0, 13.7; MS m/z 533.30 [M+H]+.
1H NMR
1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.52 (s, 2H), 4.00-3.91 (m, 1H), 3.63-3.55 (m, 1H), 3.36 (t, J = 6.9 Hz, 2H), 2.10 (d, J = 11.0 Hz, 2H), 1.97 (d, J = 10.4 Hz, 2H), 1.59 (dt, J = 15.0, 7.3 Hz, 2H), 1.47-1.25 (m, 6H), 0.97 (t, J = 7.4 Hz, 3H); MS m/z 477.25 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.39 (s, 1H), 7.64-7.53 (m, 2H), 7.14- 7.03 (m, 2H), 4.12-4.01 (m, 1H), 3.67-3.59 (m, 1H), 3.55-3.39 (m, 2H), 2.16- 2.06 (m, 2H), 2.05-1.94 (m, 2H), 1.71-1.61 (m, 2H), 1.54-1.35 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 402.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 7.64-7.57 (m ,2H), 7.13- 7.04 (m, 2H), 3.58-3.40 (m 4H), 3.11-3.02 (m, 1H), 2.08 (d, J = 10.3 Hz, 2H), 1.95 (d, J = 12.0 Hz, 2H), 1.73 (s, 1H), 1.70-1.61 (m, 2H), 1.49-1.34 (m, 4H), 1.29-1.15 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 415.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.58 (d, J = 7.43 Hz, 1H), 8.04 (s, 1H), 3.97 (d, J = 12.7 Hz, 2H), 3.82-3.80 (m, 6H), 3.56-3.47 (m, 1H), 3.33-3.25 (m, 3H), 2.70 (t, J = 11.8 Hz, 1H), 2.00-1.94 (m, 2H), 1.92-1.84 (m, 2H), 1.80-1.69 (m, 2H), 1.54- 1.44 (m, 2H), 1.35-1.23 (m, 16H), 0.82 (t, J = 7.4 Hz, 3H); MS m/z 491.40 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.73 (t, J = 5.6 Hz, 1H), 7.83 (d, J = 7.4 Hz, 1H), 7.54 (s, 1H), 4.46 (d, J = 7.8 Hz, 1H), 4.10 (d, J = 13.6 Hz, 2H), 4.01-3.90 (m, 1H), 3.75-3.62 (m, 2H), 3.45- 3.35 (m, 2H), 3.05 (t, J = 11.9 Hz, 2H), 2.13-1.96 (m, 9H), 1.66-1.57 (m, 2H), 1.43 (s, 9H), 1.41-1.33 (m, 6H), 0.93 (t, J = 7.4 Hz, 3H); MS m/z 491.35 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 8.07 (s, 1H), 7.67 (s, 4H), 5.28 (s, 1H), 3.94 (s, 1H), 3.74-3.65 (m, 4H), 3.37 (dd, J = 13.1, 6.6 Hz, 2H), 3.03-2.89 (m, 4H), 2.78-2.63 (m, 1H), 2.14- 2.01 (m, 2H), 1.88 (d, J = 10.2 Hz, 2H), 1.70 (s, 3H), 1.59-1.48 (m, 2H), 1.41- 1.22 (m, 6H), 0.92 (t, J = 7.3 Hz, 3H); MS m/z 532.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 3.97-3.87 (m, 1H), 3.87-3.75 (m, 1H), 3.59-3.50 (m, 4H), 3.29- 3.23 (m, 4H), 2.78 (td, J = 12.6, 2.8 Hz, 2H), 2.04-1.86 (m, 6H), 1.80-1.66 (m, 2H), 1.50-1.41 (m, 2H), 1.33- 1.16 (m, 6H), 0.83 (t, J = 7.3 Hz, 3H); MS m/z 391.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.39 (s, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.72-7.65 (m, 2H), 4.20 (s, 4H), 4.07 (s, 1H), 3.75-3.67 (m, 4H), 3.66- 3.57 (m, 1H), 3.00 (s, 3H), 2.98-2.94 (m, 4H), 2.20- 2.05 (m, 2H), 2.04-1.93 (m, 2H), 1.48-1.34 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.8, 153.3, 144.1, 142.4, 130.0, 128.8, 120.7, 100.3, 68.6, 66.0, 49.6, 45.9, 32.9, 29.5, 27.5; MS m/z 491.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.46 (s, 1H), 7.92-7.81 (m, 2H), 7.77-7.68 (m, 2H), 4.14- 4.02 (m, 1H), 3.76-3.66 (m, 4H), 3.68-3.59 (m, 1H), 3.51 (dd, J = 14.2, 7.0 Hz, 2H), 3.02-2.90 (m, 4H), 2.13 (d, J = 8.5 Hz, 2H), 2.00 (d, J = 9.1 Hz, 2H), 1.45 (dd, J = 18.7, 10.0 Hz, 4H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.8, 152.7, 144.4, 142.5, 130.0, 128.7, 120.5, 100.8, 68.4, 65.84, 49.7, 46.0, 36.3, 32.8, 29.3, 13.3; MS m/z 505.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.45 (s, 1H), 7.90-7.82 (m, 2H), 7.75-7.68 (m, 2H), 4.12- 3.98 (m, 1H), 3.80-3.66 (m, 4H), 3.67-3.59 (m ,1H), 3.43 (t, J = 7.1 Hz, 2H), 3.03-2.91 (m, 4H), 2.22- 2.09 (m, 2H), 2.07-1.95 (m, 2H), 1.74-1.63 (m, 2H), 1.53-1.35 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.3, 159.8, 153.2, 144.8, 142.6, 129.9, 128.7, 120.6, 100.6, 68.5, 65.9, 49.7, 46.00, 43.1, 32.8, 29.4, 22.0, 10.7; MS m/z 519.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.45 (s, 1H), 7.89-7.81 (m, 2H), 7.74-7.67 (m, 2H), 4.26- 4.15 (m, 1H), 4.13-4.02 (m, 1H), 3.75-3.68 (m, 4H), 3.68-3.60 (m, 1H), 3.00- 2.92 (m, 4H), 2.20-2.08 (m, 2H), 2.05-1.96 (m, 2H), 1.53-1.37 (m, 4H), 1.32 (s, 3H), 1.30 (s, 3H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.8, 152.0, 144.5, 142.5, 130.0, 128.9, 128.7, 120.5, 117.5, 100.7, 68.4, 65.8, 49.7, 46.0, 44.03, 32.7, 2.9.3, 22.2, 21.1; MS m/z 519.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.47 (s, 1H), 7.89-7.83 (m, 2H), 7.75-7.71 (m, 2H), 4.12- 4.03 (m, 1H), 3.76 (t, J = 5.5 Hz, 2H), 3.74-3.68 (m, 4H), 3.68-3.57 (m, 3H), 3.00-2.93 (m, 4H), 2.16- 2.08 (m, 2H), 2.04-1.95 (m, 2H), 1.50-1.38 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.9, 153.0, 144.7, 142.5, 130.1, 128.7, 120.5, 100.9, 68.4, 65.8, 59.4, 49.6, 46.0, 43.6, 32.7, 29.3; MS m/z 521.20 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.40 (s, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 4.08-3.99 (m, 1H), 3.74-3.68 (m, 4H), 3.68- 3.58 (m, 3H), 3.55 (t, J = 6.8 Hz, 2H), 3.01-2.90 (m, 4H), 2.15-2.04 (m, 2H), 2.04-1.93 (m, 2H), 1.89- 1.79 (m, 2H), 1.46-1.34 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.8, 152.9, 144.2, 142.5, 129.9, 128.8, 120.7, 100.4, 68.5, 66.0, 59.2, 49.7, 45.9, 38.6, 32.8, 31.1, 29.5; MS m/z 535.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.43 (s, 1H), 7.86-7.77 (m, 2H), 7.74-7.65 (m, 2H), 7.34- 7.24 (m, 2H), 7.05-6.95 (m, 2H), 4.56 (s, 2H), 3.97-3.85 (m, 1H), 3.76-3.66 (m, 4H), 3.64 -3.54 (m, 1H), 3.02- 2.90 (m, 4H), 2.03-1.88 (m, 4H), 1.43-1.26 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.1, 163.4, 161.0, 159.7, 152.8, 144.1, 142.4, 133.0, 130.0, 129.0, 128.9, 128.8, 120.8, 120.7, 115.48, 115.3, 100.8, 68.5, 66.0, 49.7, 45.9, 44.3, 33.0, 29.5; MS m/z 585.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.51- 8.46 (m, 1H), 7.87-7.79 (m, 2H), 7.73-7.65 (m, 2H), 7.64-7.55 (m, 2H), 7.42- 7.38 (m, 1H), 7.09-6.99 (m, 2H), 4.00-3.86 (m, 1H), 3.77-3.67 (m, 4H), 3.64- 3.56 (m, 1H), 3.03-2.91 (m, 4H), 2.15-2.05 (m, 2H), 2.05-1.92 (m, 2H), 1.45- 1.29 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 160.9, 160.4, 158.4, 142.8, 133.5, 129.6, 128.8, 122.9, 122.8, 120.6, 115.4, 115.2, 100.9, 68.7, 66.0, 49.8 45.6, 33.2, 29.8; MS m/z 571.20 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.46 (s, 1H), 7.89-7.83 (m, 2H), 7.74-7.68 (m, 2H), 4.11- 4.02 (m, 1H), 3.74-3.68 (m, 4H), 3.67-3.60 (m, 1H), 3.57 (t, J = 6.8 Hz, 2H), 3.49 (t, J = 5.9 Hz, 2H), 3.35 (s, 3H), 3.00-2.93 (m, 4H), 2.18-2.07 (m, 2H), 2.07-1.98 (m, 2H), 1.95- 1.87 (m, 2H), 1.50-1.38 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.8, 152.9, 144.5, 142.5, 130.0, 128.7, 120.6, 100.7, 70.1, 68.5, 65.9, 58.1, 49.7, 46.0, 39.0, 32.8, 29.4, 28.6; MS m/z 549.20 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.47 (s, 1H), 7.90-7.83 (m, 2H), 7.75-7.70 (m, 2H), 4.11- 4.01 (m, 1H), 4.01-3.92 (m, 2H), 3.76-3.67 (m, 4H), 3.67-3.58 (m, 1H), 3.47- 3.33 (m, 4H), 3.01-2.90 (m, 4H), 2.19-2.08 (m, 2H), 2.08-1.91 (m, 3H), 1.70 (d, J = 12.7 Hz, 2H), 1.56-1.30 (m, 6H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.8, 153.3, 144.8, 142.5, 130.0, 128.7, 120.5, 100.9, 68.4, 67.3, 65.8, 49.8, 46.9, 46.0, 34.8, 32.9, 30.5, 29.3; MS m/z 575.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.45 (s, 1H), 7.88-7.81 (m, 2H), 7.75-7.67 (m, 2H), 4.11- 3.96 (m, 4H), 3.75-3.69 (m, 4H), 3.68-3.60 (m, 1H), 3.56-3.47 (m, 2H), 3.03- 2.92 (m, 4H), 2.16-2.07 (m, 2H), 2.05-1.94 (m, 4H), 1.80-1.64 (m, 2H), 1.51- 1.35 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.0, 159.8, 152.0, 144.1, 142.4, 130.1, 128.8, 120.7, 100.8, 68.3, 66.3, 65.9, 50.0, 46.0, 32.8, 31.8, 29.4; MS m/z 561.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.45 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.7 Hz, 2H), 4.08-3.98 (m, 1H), 3.90-3.82 (m, 1H), 3.75- 3.66 (m, 4H), 3.67-3.60 (m, 1H), 3.03-2.89 (m, 4H), 2.19-2.09 (m, 2H), 2.08- 1.94 (m, 4H), 1.90-1.78 (m, 2H), 1.69 (d, J = 12.1 Hz, 1H), 1.56-1.21 (m, 9H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.1, 159.7, 144.2, 142.5, 130.1, 128.7, 120.5, 100.9, 68.4, 65.8, 51.4, 50.1, 46.0, 32.9, 31.8, 29.3, 25.1, 24.7; MS m/z 559.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.58 (s, 1H), 7.90-7.81 (m, 2H), 7.74-7.64 (m, 2H), 4.04- 3.95 (m, 1H), 3.81 (s, 8H), 3.75-3.67 (m, 4H), 3.66- 3.59 (m, 1H), 3.03-2.86 (m, 4H), 2.16-2.05 (m, 2H), 2.05-1.94 (m, 2H), 1.50- 1.32 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.7, 159.6, 154.5, 147.9, 142.7, 129.7, 128.7, 120.7, 100.7, 68.5, 66.0, 65.9, 49.3, 46.0, 44.7, 32.8, 29.5; MS m/z 547.25 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.45 (s, 1H), 7.89-7.80 (m, 2H), 7.76-7.68 (m, 2H), 7.26- 7.17 (m, 2H), 7.04-6.94 (m, 2H), 4.09-3.98 (m, 1H), 3.75-3.57 (m, 7H), 3.01- 2.88 (m, 6H), 2.19-2.08 (m, 2H), 2.07-1.97 (m, 2H), 15.3-1.36 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.1, 162.9, 160.5, 159.8, 152.9, 144.4, 142.5, 134.2, 130.1, 130.1, 130.0, 128.7, 120.6, 115.2, 115.0, 110.1, 100.9, 68.4, 65.9, 49.7, 46.0, 42.7, 34.2, 32.9, 29.4; MS m/z 599.25 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.45 (d, J = 1.9 Hz, 1H), 7.91-7.80 (m, 2H), 7.75-7.68 (m, 2H), 4.07 (dt, J = 8.9, 7.0 Hz, 1H), 3.76-3.67 (m, 4H), 3.67-3.58 (m, 1H), 3.46 (t, J = 6.7 Hz, 2H), 3.01-2.91 (m, 4H), 2.19-2.08 (m, 2H), 2.06-1.96 (m, 2H), 1.70- 1.61 (m, 2H), 1.52-1.30 (m, 10H), 0.95-0.84 (m, 3H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.8, 153.0, 144.7, 142.6, 130.0, 128.7, 120.5, 109.9, 100.7, 68.4, 65.8, 49.7, 46.0, 41.4, 32.9, 31.3, 29.4, 28.7, 26.4, 22.3, 13.3; MS m/z 561.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.45 (s, 1H), 7.90-7.80 (m, 2H), 7.76-7.67 (m, 2H), 4.09- 3.98 (m, 1H), 3.77-3.66 (m, 4H), 3.67-3.59 (m, 1H), 3.28 (d, J = 6.8 Hz, 2H), 3.05-2.89 (m, 4H), 2.19- 2.08 (m, 2H), 2.05-1.90 (m, 3H), 1.53-1.34 (m, 4H), 0.99 (s, 3H), 0.97 (s, 3H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.4, 159.9, 153.9, 145.6, 142.6, 129.9, 128.7, 120.6, 100.6, 68.5, 65.9, 49.7, 46.0, 32.9, 29.4, 28.1, 19.5; MS m/z 533.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.45 (s, 1H), 7.90-7.82 (m, 2H), 7.75-7.68 (m, 2H), 4.11- 4.03 (m, 1H), 3.76-3.67 (m, 4H), 3.67-3.56 (m, 3H), 3.50 (t, J = 6.9 Hz, 2H), 3.02-2.29 (m, 4H), 2.18- 2.08 (m, 2H), 2.07-1.96 (m, 2H), 1.78-1.68 (m, 2H), 1.66-1.56 (m, 2H), 1.54- 1.34 (m, 4H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 164.2, 159.8, 153.0, 144.7, 142.5, 130.0, 128.7, 120.6, 100.7, 68.4, 65.9, 61.2, 49.7, 46.00, 41.2, 32.8, 29.5, 29.4, 25.3; MS m/z 549.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.77 (d, J = 8.8 Hz, 2H), 7.63 (dd, J = 9.1, 2.0 Hz, 2H), 4.17 (s, 4H), 3.99-3.87 (m, 1H), 3.74-3.62 (m, 8H), 3.60-3.46 (m, 3H), 2.97- 2.87 (m, 4H), 2.73-2.45 (m, 6H), 2.11-1.98 (m, 2H), 1.98-1.88 (m, 2H), 1.40- 1.25 (m, 4H); MS m/z 590.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.50-8.45 (m, 1H), 7.89 (d, J = 8.7 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 4.16-4.07 (m, 1H), 3.73-3.67 (m, 4H), 3.66- 3.57 (m, 1H), 3.00-2.90 (m, 4H), 2.15-2.06 (m, 2H), 2.03-1.95 (m, 2H), 1.51- 1.36 (m, 4H); MS m/z 477.20 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 7.81-7.75 (m, 2H), 7.70- 7.62 (m, 2H), 7.33 (d, J = 1.3 Hz, 1H), 3.93 (t, J = 6.5 Hz, 3H), 3.72-3.63 (m, 4H), 3.60-3.50 (m, 1H), 3.36 (t, J = 6.7 Hz, 2H), 2.94 (s, 7H), 2.11-2.00 (m, 2H), 2.00- 1.91 (m, 2H), 1.47-1.29 (m, 4H); MS m/z 538.20 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 9.37 (d, J = 7.4 Hz, 1H), 8.34 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 4.01-3.95 (m, 1H), 3.72-3.63 (m, 4H), 3.63-3.52 (m, 1H), 3.46 (t, J = 7.2 Hz, 2H), 2.99-2.80 (m, 4H), 2.13-1.85 (m, 4H), 1.47 (dd, J = 14.3, 7.1 Hz, 2H), 1.43-1.28 (m, 4H), 0.72-0.58 (m, 1H), 0.46- 0.36 (m, 2H), 0.07-0.05 (m, 2H); MS m/z 545.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.40 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 4.06-3.93 (m, 1H), 3.71-3.60 (m, 4H), 3.60-3.54 (m, 1H), 3.49 (t, J = 7.1 Hz, 2H), 2.98-2.85 (m, 4H), 2.23-2.11 (m, 2H), 2.10-2.01 (m, 2H), 2.00- 1.81 (m, 4H), 1.46-1.27 (m, 4H); MS m/z 487.25 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.49 (d, J = 1.8 Hz, 1H), 7.91 (dd, J = 8.8, 1.7 Hz, 2H), 7.78-7.71 (m, 2H), 3.74-3.65 (m, 4H), 3.63-3.55 (m, 2H), 3.51 (t, J = 6.5 Hz, 2H), 3.43 (d, J = 12.5 Hz, 2H), 3.05-2.88 (m, 6H), 2.12-1.93 (m, 3H), 1.70-1.59 (m, 2H), 1.59- 1.37 (m, 4H), 1.03-0.90 (m, 3H); MS m/z 532.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 3.80-3.65 (m, 4H), 3.60-3.43 (m, 4H), 3.12-3.04 (m, 1H), 3.03- 2.91 (m, 4H), 2.09 (d, J = 10.6 Hz, 2H), 1.95 (d, J = 11.9 Hz, 2H), 1.78-1.60 (m, 3H), 1.53-1.34 (m, 4H), 1.31-1.12 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 546.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.95-7.86 (m, 2H), 7.82- 7.73 (m, 2H), 4.50-4.38 (m, 1H), 3.74-3.68 (m, 4H), 3.59-3.41 (m, 4H), 3.25- 3.14 (m, 2H), 3.01-2.93 (m, 4H), 2.41-2.27 (m, 2H), 1.95-1.80 (m, 2H), 1.73- 1.59 (m, 2H), 1.53-1.38 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 518.30 [M + H]+.
1H NMR (400 MHz, CDCl3 + CD3OD) δ 9.98 (s, 1H), 9.41 (t, J = 5.5 Hz, 1H), 8.57 (s, 1H), 8.19 (t, J = 5.2 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 3.72-3.63 (m, 4H), 3.50 (dd, J = 12.8, 6.7 Hz, 2H), 3.41-3.33 (m, 2H), 3.08-3.00 (m, 2H), 2.97- 2.86 (m, 4H), 1.67-1.59 (m, 2H), 1.59-1.51 (m, 2H), 1.48-1.41 (m, 2H), 1.41- 1.25 (m, 14H), 0.88 (t, J = 7.3 Hz, 3H); MS m/z 634.40 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.83-9.59 (m, 1H), 8.69- 8.49 (m, 1H), 8.16-7.98 (m, 2H), 7.98-7.83 (m, 2H), 4.25-4.11 (m, 7H), 3.96- 3.87 (m, 3H), 3.80-3.69 (m, 2H), 3.68-3.57 (m, 2H), 3.57-3.44 (m, 2H), 3.22- 3.12 (m, 3H), 3.10-2.98 (m, 2H), 1.92-1.75 (m, 5H), 1.67-152 (m, 5H), 1.25- 0.97 (m, 3H); MS m/z 534.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz, 2H), 4.14-3.97 (m, 3H), 3.92-3.86 (m, 2H), 3.73-3.67 (m, 4H), 3.63- 3.41 (m, 6H), 3.38-3.33 (m, 2H), 2.99-2.91 (m, 4H), 1.66 (dt, J = 14.8, 7.3 Hz, 2H), 1.45 (dt, J = 15.0, 7.4 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 548.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 9.53 (d, J = 7.3 Hz, 1H), 8.66 (s, 1H), 8.21 (t, J = 5.4 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 4.33-4.24 (m, 1H), 4.04- 3.97 (m, 2H), 3.77-3.67 (m, 4H), 3.60-3.49 (m, 2H), 3.47-3.39 (m, 2H), 3.05- 2.90 (m, 4H), 2.03 (d, J = 10.9 Hz, 2H), 1.75-1.64 (m, 2H), 1.65-1.57 (m, 2H), 1.45-1.33 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); MS m/z 519.25 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.80 (t, J = 5.9 Hz, 1H), 9.55 (s, 1H), 8.76 (s, 1H), 8.60 (t, J = 5.1 Hz, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 8.7 Hz, 2H), 4.13-4.03 (m, 2H), 3.98 (s, 4H), 3.76-3.69 (m, 4H), 3.44-3.35 (m, 4H), 3.02- 2.88 (m, 5H), 1.61 (dt, J = 15.0, 7.3 Hz, 2H), 1.39 (dq, J = 14.8, 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H); MS m/z 548.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 8.48 (s, 1H), 7.86 (s, 1H), 7.83 (s, 2H), 7.71 (d, J = 8.7 Hz, 2H), 3.88 (t, J = 5.2 Hz, 4H), 3.76-3.70 (m, 4H), 3.63 (t, J = 5.2 Hz, 4H), 3.37 (dd, J = 12.9, 7.0 Hz, 2H), 3.32 (s, 6H), 3.02-2.94 (m, 4H), 1.58 (dt, J = 15.0, 7.5 Hz, 2H), 1.36 (dt, J = 14.9, 7.4 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H); MS m/z 551.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 9.69 (s, 1H), 8.60 (s, 1H), 8.38 (t, J = 5.3 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 3.85-3.77 (m, 2H), 3.77-3.69 (m, 8H), 3.69- 3.61 (m, 2H), 3.40 (dd, J = 12.9, 6.9 Hz, 2H), 3.02-2.92 (m, 4H), 1.64-1.52 (m, 2H), 1.37 (dq, J = 14.5, 7.3 Hz, 2H), 0.92 (t, J = 7.3 Hz, 3H); MS m/z 523.25 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 9.55 (t, J = 5.6 Hz, 1H), 8.57 (s, 1H), 8.16 (t, J = 5.2 Hz, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 3.77-3.67 (m, 4H), 3.43- 3.33 (m, 4H), 3.02-2.93 (m, 4H), 2.01-1.87 (m, 1H), 1.69-1.52 (m, 2H), 1.46- 1.31 (m, 2H), 1.03-0.90 (m, 9H); MS m/z 491.25 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.69 (s, 2H), 8.75 (s, 1H), 8.30 (t, J = 5.4 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 4.72-4.64 (m, 1H), 3.80- 3.67 (m, 5H), 3.59-3.51 (m, 2H), 3.50-3.40 (m, 2H), 3.04-2.92 (m, 4H), 2.36- 2.26 (m, 1H), 2.08-1.98 (m, 1H), 1.67-1.59 (m, 2H), 1.47 (s, 9H), 1.43-1.35 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); MS m/z 604.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.75 (t, J = 5.8 Hz, 1H), 9.33 (s, 1H), 8.87 (s, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 3.90-3.83 (m, 1H), 3.77- 3.69 (m, 4H), 3.58-3.41 (m, 4H), 3.13-2.82 (m, 6H), 2.80-2.63 (m, 1H), 1.96- 1.84 (m, 2H), 1.77-1.68 (m, 1H), 1.67-1.49 (m, 3H), 1.47-1.35 (m, 10H), 0.96 (t, J = 7.3 Hz, 3H); MS m/z 632.35 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.71 (s, 2H), 8.75 (s, 1H), 8.30 (t, J = 5.3 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 4.68 (s, 1H), 3.81-3.67 (m, 5H), 3.60-3.50 (m, 2H), 3.48-3.39 (m, 2H), 3.05- 2.91 (m, 4H), 2.36-2.25 (m, 1H), 2.08-1.96 (m, 1H), 1.68-1.56 (m, 2H), 1.47 (s, 9H), 1.44-1.31 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H); MS m/z 604.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.71 (t, J = 5.5 Hz, 1H), 9.52 (s, 1H), 8.68 (s, 1H), 8.04 (s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.71 (d, J = 8.6 Hz, 2H), 3.79-3.64 (m, 6H), 3.53 (t, J = 5.7 Hz, 2H), 3.46 (dd, J = 12.8, 6.9 Hz, 2H), 3.39 (s, 3H), 3.07-2.91 (m, 4H), 1.99-1.88 (m, 2H), 1.67-1.56 (m, 2H), 1.39 (dq, J = 14.6, 7.3 Hz, 2H), 0.94 (t, J = 7.3 Hz, 3H); MS m/z 507.20 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 9.42 (t, J = 6.0 Hz, 1H), 8.50 (s, 1H), 8.27 (s, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 3.75-3.71 (m, 4H), 3.68 (t, J = 6.3 Hz, 2H), 3.58 (dd, J = 12.8, 6.6 Hz, 2H), 3.43 (dd, J = 13.0, 6.8 Hz, 2H), 3.05-2.91 (m, 4H), 1.75-1.68 (m, 2H), 1.66- 1.57 (m, 4H), 1.54-1.45 (m, 2H), 1.43-1.34 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); MS m/z 521.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.94 (s, 1H), 9.49 (t, J = 5.5 Hz, 1H), 8.64 (s, 1H), 8.14 (t, J = 5.4 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 4.01-3.92 (m, 2H), 3.79- 3.67 (m, 4H), 3.65-3.56 (m, 2H), 3.48-3.34 (m, 4H), 3.05-2.90 (m, 4H), 1.68- 1.55 (m, 6H), 1.45-1.27 (m, 4H), 0.93 (t, J = 7.3 Hz, 3H); MS m/z 547.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.25 (s, 1H), 9.58 (t, J = 5.7 Hz, 1H), 8.59 (s, 1H), 8.20 (t, J = 5.4 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 4.01 (dd, J = 11.3, 3.6 Hz, 2H), 3.81-3.62 (m, 4H), 3.54-3.29 (m, 6H), 3.07- 2.87 (m, 4H), 1.98-1.84 (m, 1H), 1.70-1.63 (m, 2H), 1.64-1.53 (m, 2H), 1.49- 1.29 (m, 4H), 0.93 (t, J = 7.3 Hz, 3H); MS m/z 533.25 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.90 (s, 1H), 9.47 (s, 1H), 8.51 (s, 1H), 8.31-8.20 (m, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 3.82-3.65 (m, 4H), 3.52-3.29 (m, 4H), 3.10- 2.87 (m, 4H), 1.66-1.54 (m, 2H), 1.42-1.33 (m, 2H), 1.19-1.06 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H), 0.70-0.58 (m, 2H), 0.36-0.27 (m, 2H); MS m/z 489.20 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 9.55 (t, J = 5.5 Hz, 1H), 8.55 (s, 1H), 8.22 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 3.80-3.71 (m ,4H), 3.71-3.59 (m, 2H), 3.53- 3.39 (m, 2H), 3.06-2.93 (m, 4H), 1.72-1.52 (m, 4H), 1.50-1.30 (m, 2H), 1.02- 0.87 (m, 3H), 0.80-0.67 (m, 1H), 0.58-0.45 (m, 2H), 0.17-0.06 (m, 2H); MS m/z 503.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 9.48 (t, J = 5.5 Hz, 1H), 8.53 (s, 1H), 8.28 (t, J = 4.9 Hz, 1H), 7.82 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.6 Hz, 2H), 3.76-3.69 (m, 6H), 3.65- 3.57 (m, 2H), 3.47-3.36 (m, 2H), 3.04-2.90 (m, 4H), 1.82-1.74 (m, 2H), 1.71- 1.64 (m, 2H), 1.62-1.54 (m, 2H), 1.43-1.33 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); MS m/z 507.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.90-7.61 (m, 4H), 7.23-7.13 (m, 2H), 7.05-6.95 (m, 2H), 3.78- 3.70 (m, 6H), 3.44 (dd, J = 13.1, 6.4 Hz, 2H), 3.06-2.95 (m, 4H), 2.95-2.85 (m, 2H), 1.72-1.48 (m, 2H), 1.49- 1.27 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H); MS m/z 557.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.13 (s, 1H), 9.43 (d, J = 6.9 Hz, 1H), 8.54 (s, 1H), 8.25 (t, J = 5.4 Hz, 1H), 7.83 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 4.49-4.36 (m, 1H), 3.79- 3.66 (m, 4H), 3.43 (dd, J = 12.9, 6.9 Hz, 2H), 3.06-2.94 (m, 4H), 2.15-2.01 (m, 2H), 1.83-1.74 (m, 2H), 1.74- 1.65 (m, 2H), 1.65-1.54 (m, 4H), 1.46-1.32 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); MS m/z 503.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.15 (s, 1H), 9.37 (d, J = 4.1 Hz, 1H), 8.55 (s, 1H), 8.39 (t, J = 5.5 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 3.77-3.66 (m, 4H), 3.48 (dd, J = 13.0, 6.9 Hz, 2H), 3.09-3.01 (m, 1H), 3.01- 2.92 (m, 5H), 1.67-1.56 (m, 2H), 1.43-1.31 (m, 2H), 0.95-0.89 (m, 4H), 0.76- 0.62 (m, 2H); MS m/z 475.20 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.71-8.51 (m, 2H), 8.51-8.40 (m, 1H), 8.04-7.90 (m, 1H), 7.90- 7.74 (m, 2H), 7.74-7.61 (m, 2H), 7.60-7.50 (m, 1H), 4.90-4.77 (m, 2H), 3.78- 3.61 (m, 4H), 3.40-3.24 (m, 2H), 3.04-2.85 (m, 4H), 1.57-1.36 (m, 2H), 1.38- 1.16 (m, 2H), 0.93-0.75 (m, 3H); MS m/z 526.25 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.25 (t, J = 4.8 Hz, 1H), 7.94 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 3.78 (s, 8H), 3.76-3.70 (m, 4H), 3.38 (dd, J = 12.7, 7.0 Hz, 2H), 3.05-2.90 (m, 4H), 1.62-1.51 (m, 2H), 1.41- 1.30 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H); MS m/z 505.25 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.98 (s, 1H), 9.42 (d, J = 7.6 Hz, 1H), 8.58 (s, 1H), 8.16 (t, J = 5.2 Hz, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 4.12-4.01 (m, 1H), 3.78- 3.69 (m, 4H), 3.45-3.36 (m, 2H), 3.05-2.93 (m, 4H), 2.06-1.93 (m, 2H), 1.85- 1.72 (m, 2H), 1.70-1.43 (m, 3H), 1.50-1.25 (m, 7H), 0.93 (t, J = 7.3 Hz, 3H); MS m/z 517.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 9.51 (t, J = 5.7 Hz, 1H), 8.54 (s, 1H), 8.23 (s, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 3.78-3.66 (m, 4H), 3.46-3.34 (m, 4H), 3.03- 2.94 (m ,4H), 1.83-1.73 (m, 4H), 1.72-1.63 (m, 2H), 1.62-1.55 (m, 2H), 1.41- 1.33 (m, 2H), 1.30-1.14 (m, 3H), 1.08-0.95 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H); MS m/z 531.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.57 (s, 1H), 7.91 (d, J = 8.7 Hz, 2H), 7.76 (dd, J = 6.2, 4.7 Hz, 2H), 3.75-3.64 (m, 5H), 3.56- 3.50 (m, 2H), 3.48-3.41 (m, 2H), 3.32-3.27 (m, 4H), 2.99-2.91 (m, 4H), 2.60- 2.47 (m, 1H), 2.27-2.15 (m, 1H), 1.72-1.61 (m, 2H), 1.51-1.37 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 504.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 9.83 (t, J = 5.4 Hz, 1H), 9.32-9.18 (m, 1H), 8.74 (s, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.4 Hz, 2H), 3.71 (s, 4H), 3.62-3.50 (m, 3H), 3.37 (ddd, J = 30.0, 12.9, 5.7 Hz, 3H), 2.95 (s, 5H), 2.86-2.74 (m, 1H), 2.49-2.34 (m, 1H), 2.09-1.83 (m, 3H), 1.67- 1.53 (m, 2H), 1.48-1.24 (m, 3H), 0.93 (t, J = 7.3 Hz, 3H); MS m/z 532.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.56 (s, 1H), 7.94-7.87 (m, 2H), 7.79- 7.71 (m, 2H), 3.74-3.63 (m, 5H), 3.56-3.50 (m, 3H), 3.47-3.39 (m, 3H), 3.00- 2.90 (m, 4H), 2.59-2.46 (m, 1H), 2.27-2.15 (m, 1H), 1.72-1.61 (m, 2H), 1.53- 1.38 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 504.30 [M + H]+.
To a solution of 2,4-dichloropyrimidine-5-carbonyl chloride (500 mg, 2.38 mmol) in dichloromethane (30 mL) was added methanol (87.6 mg, 2.73 mmol) and diisopropylethylamine (369 mg, 2.86 mmol) at 0° C. The resulting mixture was stirred for 1 h at 0° C. Then the solvent was removed. The residue (461 mg, 94%) was dissolved in IPA (20 mL) and followed by the addition of trans-4-aminocyclohexanol (301.6 mg, 2.62 mmol) then DIEA (461.4 mg, 3.57 mmol) dropwisely. The resulting mixture was stirred at 0° C. for 90 min. After which butylamine (208.8 mg, 2.86 mmol) was added, followed by DIEA (461.4 mg, 3.57 mmol). The resulting mixture was stirred at room temperature for 3 h. Water was then added. The resulting mixture was extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to provide methyl 2-(butylamino)-4-(((trans-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylate (682.6 mg, 89% over 3 steps). 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.77 (s, 1H), 6.29 (s, 1H), 4.81-4.64 (m, 1H), 4.51 (s, 3H), 4.46-4.38 (m, 1H), 4.13-4.11 (m, 2H), 2.89-2.81 (m, 2H), 2.74 (d, J=9.7 Hz, 2H), 2.35-2.25 (m, 2H), 2.23-2.00 (m, 6H), 1.67 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 167.9, 162.5, 161.3, 160.3, 95.5, 69.7, 51.2, 48.3, 41.1, 33.8, 31.7, 30.3, 20.1, 13.8; MS m/z 323.20 [M+H]+.
A mixture of methyl 2-(butylamino)-4-(((trans-4-hydroxycyclohexyl)amino) pyrimidine-5-carboxylate (682.6 mg, 2.12 mmol) and lithium hydroxide monohydrate (888.4 mg, 21.2 mmol) in a mixture of methanol and water (25 mL, 3:2, v/v) was heated at reflux for 2 h. Then the reaction mixture was cooled to room temperature and acidified by a 4.0N solution of HCl (4N) to PH 3. The resulting mixture was extracted with EtOAc (4×). The combined organic layers were dried (Na2SO4) and concentrated to provide 2-(butylamino)-4-(((1r,4r)-4-hydroxycyclohexyl)amino)pyrimidine-5-carboxylic acid (647.1 mg, 99%), which was used in the next step without further purifications. MS m/z 309.30 [M+H]+.
A solution of the acid (61 mg, 0.20 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU, 81.4 mg, 0.25 mmol, 1.3 eq) and N,N-diisopropylethylamine (DIEA, 77.5 mg, 0.60 mmol, 3.0 eq) in anhydrous DMF (3.0 mL) and was added 4-fluorobenzylamine (37.5 mg, 0.30 mmol, 1.5 eq) in DMF (1.0 mL) dropwisely at room temperature. The resulting mixture was stirred for overnight, then diluted with EtOAc (15 mL) and washed with water (3×). The organic layer was dried (Na2SO4) and concentrated. The residue was purified on HPLC to give the title compound (61.5 mg, 74%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.57 (d, J=7.4 Hz, 1H), 8.77 (s, 1H), 8.13 (s, 1H), 7.40-7.31 (m, 1H), 7.29-7.22 (m, 3H), 7.00 (t, J=8.6 Hz, 2H), 4.44 (d, J=5.2 Hz, 2H), 4.00 (s, 1H), 3.77-3.62 (m, 1H), 3.40 (dd, J=13.0, 6.9 Hz, 2H), 2.15-2.09 (m, 2H), 2.04 (d, J=7.6 Hz, 2H), 1.66-1.54 (m, 2H), 1.49-1.33 (m, 6H), 0.94 (t, J=7.3 Hz, 3H); MS m/z 416.30 [M+H]+.
1H NMR
1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 3.87 (s, 6H), 3.47 (t, J = 5.9 Hz, 3H), 3.25-3.19 (m, 2H), 3.15 (t, J = 6.6 Hz, 2H), 1.96 (d, J = 10.9 Hz, 2H), 1.85 (d, J = 10.3 Hz, 2H), 1.53-1.39 (m, 6H), 1.30-1.17 (m, 6H), 0.80 (t, J = 7.3 Hz, 3H); MS m/z 380.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.50 (d, J = 7.4 Hz, 1H), 9.38 (t, J = 5.4 Hz, 1H), 7.82 (s, 1H), 7.09 (s, 1H), 4.03- 3.91 (m, 1H), 3.73-3.64 (m, 1H), 3.50 (t, J = 5.5 Hz, 2H), 3.45-3.35 (m, 4H), 3.34 (s, 3H), 2.12-2.05 (m, 2H), 2.05-1.98 (m, 2H), 1.84- 1.77 (m, 2H), 1.63-1.55 (m, 2H), 1.45-1.31 (m, 6H), 0.91 (t, J = 7.4 Hz, 3H); MS m/z 380.30 [M +H]+.
1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.31 (d, J = 8.3 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 3.64 (t, J = 7.0 Hz, 2H), 3.55-3.46 (m, 1H), 3.30 (t, J = 7.2 Hz, 2H), 3.25-3.18 (m, 1H), 2.69 (t, J = 7.0 Hz, 2H), 2.01-1.94 (m, 2H), 1.90-1.85 (m, 2H), 1.54-1.44 (m, 2H), 1.33- 1.22 (m, 6H), 0.82 (t, J = 7.3 Hz, 3H); MS m/z 428.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 6.0 Hz, 2H), 8.11 (s, 1H), 7.27 (s, 2H), 7.21 (d, J = 6.0 Hz, 2H), 4.44 (s, 2H), 3.94-3.83 (m, 1H), 3.55 (s, 4H), 2.09-1.98 (m, 2H), 1.96-1.88 (m, 2H), 1.55-1.45 (m, 2H), 1.39- 1.21 (m, 6H), 0.88 (t, J = 7.3 Hz, 3H); MS m/z 399.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 9.62 (d, J = 7.3 Hz, 1H), 8.34 (s, 1H), 8.24 (s, 1H), 7.18-7.13 (m, 2H), 7.01- 6.95 (m, 2H), 6.82-6.68 (m, 1H), 4.55-4.36 (m, 1H), 4.07-3.93 (m, 1H), 3.81- 3.67 (m, 1H), 3.64-3.50 (m, 2H), 3.43 (dd, J = 13.5, 6.6 Hz, 2H), 2.85 (t, J = 7.4 Hz, 2H), 2.16-2.01 (m, 4H), 1.69-1.55 (m, 2H), 1.53- 1.34 (m, 6H), 0.95 (t, J = 7.4 Hz, 3H); MS m/z 430.30 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 9.49 (d, J = 7.5 Hz, 1H), 8.08 (s, 1H), 3.89-3.81 (m, 4H), 3.72- 3.66 (m, 3H), 3.56-3.50 (m, 1H), 3.42-3.35 (m, 1H), 3.32-3.22 (m, 6H), 3.03- 2.96 (m, 2H), 2.84 (s, 2H), 2.08-1.94 (m, 2H), 1.94- 1.85 (m, 4H), 1.54-1.46 (m, 2H), 1.36-1.20 (m, 6H), 0.83 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CD3OD + CDCl3) δ 169.4, 163.7, 156.7, 146.9, 104.1, 72.6, 67.7, 59.0, 55.7, 45.0, 40.3, 36.9, 34.7, 33.4, 27.2, 23.8, 17.4; MS m/z 435.35 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.08 (s, 1H), 3.90-3.64 (m, 8H), 3.46-3.37 (m, 3H), 3.35- 3.21 (m, 5H), 3.04-2.94 (m, 2H), 2.83 (s, 1H), 1.97-1.86 (m, 2H), 1.57-1.45 (m, 4H), 1.36-1.23 (m, 4H), 0.84 (q, J = 7.3 Hz, 6H); 13C NMR (101 MHz, CD3OD+ CDCl3) δ 161.4, 156.3, 148.7, 138.6, 96.1, 51.0, 47.9, 36.9, 36.5, 32.3, 26.5, 19.2, 15.9, 15.7, 9.4; MS m/z 393.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.80-8.74 (m, 1H), 8.49 (td, J = 7.9, 1.6 Hz, 1H), 8.40 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.93- 7.87 (m, 1H), 4.84 (s, 2H), 4.11-3.99 (m, 1H), 3.68- 3.55 (m, 1H), 3.48 (t, J = 7.1 Hz, 2H), 2.19-1.90 (m, 4H), 1.73-1.57 (m, 2H), 1.51- 1.33 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 399.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.88 (M, 1H), 8.78 (d, J = 5.7 Hz, 1H), 8.64-8.57 (m, 1H), 8.34 (s, 1H), 8.08-8.02 (m, 1H), 4.70 (s, 2H), 4.11-3.99 (m, 1H), 3.69-3.57 (m, 1H), 3.47 (t, J = 7.1 Hz, 2H), 2.21-1.91 (m, 4H), 1.71- 1.57 (m, 2H), 1.52-1.33 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H); MS m/z 399.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.59-7.52 (m, 4H), 4.56- 4.50 (m, 2H), 4.13-3.99 (m, 1H), 3.68-3.56 (m, 1H), 3.46 (dd, J = 13.1, 6.2 Hz, 2H), 3.26 (s, 6H), 2.25-2.05 (m, 2H), 2.00 (d, J = 9.3 Hz, 2H), 1.73-1.55 (m, 2H), 1.45 (td, J = 14.8, 7.3 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 441.35 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.27 (s, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.65- 7.52 (m, 2H), 7.46 (t, J = 7.5 Hz, 1H), 4.70 (s, 2H), 4.17- 3.96 (m, 1H), 3.72-3.50 (m, 2H), 3.45 (dd, J = 33.1, 26.3 Hz, 2H), 3.31 (dt, J = 3.3, 1.6 Hz, 4H), 2.11 (d, J = 11.2 Hz, 2H), 2.00 (d, J = 10.6 Hz, 2H), 1.65 (dt, J = 14.8, 7.5 Hz, 2H), 1.56-1.15 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 466.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.64 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 4.57 (s, 2H), 4.11-4.00 (m, 1H), 3.71-3.57 (m, 1H), 3.51- 3.42 (m, 2H), 2.18-1.95 (m, 4H), 1.71-1.58 (m, 2H), 1.52-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 466.25 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 7.61-7.57 (m, 4H), 7.45- 7.39 (m, 4H), 7.35-7.29 (m, 1H), 4.53 (s, 2H), 4.10-4.00 (m, 1H), 3.70-3.58 (m, 2H), 3.52-3.40 (m, 2H), 2.17- 1.95 (m, 4H), 1.71-1.59 (m, 2H), 1.51-1.38 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 474.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.24 (t, J = 7.9 Hz, 1H), 6.93- 6.87 (m, 2H), 6.85-6.80 (m, 1H), 4.46 (s, 2H), 4.10-3.98 (m, 1H), 3.78 (s, 3H), 3.69- 3.57 (m, 1H), 3.47 (t, J = 6.9 Hz, 2H), 2.11 (d, J = 10.6 Hz, 2H), 2.00 (d, J = 10.2 Hz, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.52-1.33 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 428.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 6.48 (d, J = 2.3 Hz, 2H), 6.39 (t, J = 2.3 Hz, 1H), 4.42 (s, 2H), 4.10-3.99 (m, 2H), 3.76 (s, 6H), 3.70-3.56 (m, 2H), 3.52-3.42 (m, 2H), 2.17- 2.06 (m, 2H), 2.06-1.96 (m, 2H), 1.65 (dt, J = 15.1, 7.5 Hz, 2H), 1.54-1.36 (m, 6H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 458.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 7.17 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.48 (dd, J = 8.3, 2.4 Hz, 1H), 4.40 (s, 2H), 4.10-3.99 (m, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.52-3.42 (m, 2H), 2.16- 2.07 (m, 2H), 2.04-1.96 (m, 2H), 1.64 (dt, J = 14.8, 7.6 Hz, 2H), 1.43 (dd, J = 15.0, 7.2 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 458.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.60 (s, 1H), 7.56-7.49 (m, 1H), 7.44 (t, J = 6.8 Hz, 2H), 4.55 (s, 2H), 4.10-4.01 (m, 1H), 3.75 (bs, 4H), 3.69-3.57 (m, 2H), 3.48 (t, J = 6.9 Hz, 2H), 2.33-2.24 (m, 4H), 2.17- 2.05 (m, 2H), 2.05-1.94 (m, 2H), 1.65 (dt, J = 12.6, 7.6 Hz, 2H), 1.53-1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 467.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 4.53 (s, 2H), 4.50 (s, 2H), 4.10-3.99 (m, 1H), 3.76-3.54 (m, 8H), 3.48 (t, J = 7.0 Hz, 2H), 3.01 (s, 3H), 2.16-2.06 (m, 2H), 2.04-1.96 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.51- 1.36 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 510.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.54 (d, J = 7.4 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.23 (dtd, J = 22.9, 7.3, 1.2 Hz, 2H), 6.72 (s, 1H), 4.65 (s, 2H), 4.12-4.00 (m, 2H), 3.68- 3.60 (m, 2H), 3.50-3.42 (m, 2H), 2.17-1.95 (m, 4H), 1.65 (dt, J = 14.9, 7.3 Hz, 2H), 1.53-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 438.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.65 (d, J = 2.7 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.37 (s, 1H), 8.23 (dd, J = 8.6, 2.2 Hz, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.89 (d, J = 1.6 Hz, 1H), 6.65 (dd, J = 2.6, 1.8 Hz, 1H), 4.59 (s, 2H), 4.10-4.00 (m, 1H), 3.67-3.57 (m, 2H), 3.47 (t, J = 6.9 Hz, 2H), 2.16-2.06 (m, 2H), 2.05-1.93 (m, 2H), 1.65 (dt, J = 12.6, 7.6 Hz, 2H), 1.52-1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 465.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.47 (dd, J = 8.9, 2.2 Hz, 1H), 8.42 (s, 1H), 8.37 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 4.58 (s, 2H), 4.11-3.98 (m, 1H), 3.68-3.57 (m, 1H), 3.47 (t, J = 7.1 Hz, 2H), 2.63 (q, J = 7.5 Hz, 2H), 2.17- 1.94 (m, 4H), 1.65 (dt, J = 12.6, 7.6 Hz, 2H), 1.50-1.34 (m, 6H), 1.24 (t, J = 7.5 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 470.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.69 (d, J = 1.8 Hz, 1H), 8.48 (dd, J = 8.5, 2.1 Hz, 1H), 8.43 (s, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.04 (dd, J = 3.9, 1.1 Hz, 1H), 7.93 (dd, J = 5.0, 1.1 Hz, 1H), 7.35 (dd, J = 5.0, 3.9 Hz, 1H), 4.66 (s, 2H), 4.10-3.99 (m, 1H), 3.66- 3.57 (m, 1H), 3.48 (t, J = 7.0 Hz, 2H), 2.18-2.04 (m, 2H), 2.04-1.94 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.50- 1.33 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 481.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 1.7 Hz, 1H), 8.53 (dd, J = 8.6, 2.0 Hz, 1H), 8.43 (s, 1H), 8.29 (d, J = 8.6 Hz, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 3.7 Hz, 1H), 6.83 (dd, J = 3.7, 1.8 Hz, 1H), 4.66 (s, 2H), 4.12-4.00 (m, 1H), 3.66-3.57 (m, 2H), 3.48 (t, J = 7.1 Hz, 2H), 2.16-2.04 (m, 2H), 2.04- 1.92 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.54-1.32 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 465.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.61-7.54 (m, 2H), 7.53- 7.47 (m, 3H), 4.34 (s, 2H), 4.14-3.98 (m, 2H), 3.69- 3.58 (m, 2H), 3.59-3.50 (m, 2H), 3.50-3.41 (m, 2H), 3.25-3.10 (m, 2H), 2.25- 2.05 (m, 4H), 2.05-1.92 (m, 3H), 1.64 (dt, J = 15.0, 7.5 Hz, 2H), 1.52-1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 481.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 4.13-3.96 (m, 3H), 3.64- 3.50 (m, 4H), 3.50-3.37 (m, 3H), 3.13 (t, J = 11.9 Hz, 2H), 2.86 (s, 3H), 2.25-1.84 (m, 10H), 1.63 (dt, J = 14.9, 7.5 Hz, 2H), 1.49-1.33 (m, 6H), 0.97 (t, J = 7.4 Hz, 3H); MS m/z 405.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 4.11-3.96 (m, 1H), 3.85- 3.71 (m, 1H), 3.69-3.59 (m, 1H), 3.52-3.42 (m, 2H), 2.17-2.05 (m, 2H), 2.05- 1.94 (m, 2H), 1.95-1.87 (m, 2H), 1.87-1.75 (m, 2H), 1.73-1.58 (m, 3H), 1.51- 1.14 (m, 12H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 390.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 4.10-3.97 (m, 1H), 3.70- 3.59 (m, 1H), 3.53-3.41 (m, 2H), 3.13 (d, J = 7.0 Hz, 2H), 2.16-1.94 (m, 4H), 1.82-1.71 (m, 4H), 1.71- 1.51 (m, 4H), 1.50-1.35 (m, 6H), 1.35-1.18 (m, 4H), 0.99 (dd, J = 9.7, 5.0 Hz, 5H); MS m/z 404.35 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 4.18 (s, 2H), 4.10-3.99 (m, 1H), 3.67-3.59 (m, 1H), 3.61- 3.53 (m, 2H), 3.53-3.43 (m, 4H), 2.17-1.95 (m, 4H), 1.75-1.60 (m, 6H), 1.60- 1.53 (m, 2H), 1.52-1.33 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 433.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 4.10-3.98 (m, 1H), 3.94 (dd, J = 11.5, 2.6 Hz, 2H), 3.69- 3.58 (m, 1H), 3.52-3.44 (m, 2H), 3.40 (td, J = 11.8, 2.1 Hz, 2H), 3.20 (d, J = 6.9 Hz, 2H), 2.17-1.96 (m, 4H), 1.90-1.77 (m, 1H), 1.71- 1.60 (m, 4H), 1.53-1.37 (m, 6H), 1.37-1.24 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 406.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 4.11-4.00 (m, 3H), 3.99- 3.86 (m, 2H), 3.75 (t, J =5.8 Hz, 2H), 3.71-3.60 (m, 3H), 3.48 (t, J = 7.1 Hz, 2H), 3.40 (t, J = 5.8 Hz, 2H), 3.20 (td, J = 12.3, 3.8 Hz, 2H), 2.18- 1.96 (m, 4H), 1.65 (dt, J = 12.6, 7.6 Hz, 2H), 1.55-1.33 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 421.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.42 (s, 1H), 7.30 (t, J = 2.2 Hz, 1H), 7.25 (t, J = 8.1 Hz, 1H), 7.18-7.13 (m, 1H), 6.74 (ddd, J = 8.2, 2.5, 0.8 Hz, 1H), 4.16-4.04 (m, 1H), 3.80 (s, 3H), 3.70-3.59 (m, 2H), 3.50 (t, J = 7.0 Hz, 2H), 2.20-2.07 (m, 2H), 2.07-1.96 (m, 2H), 1.67 (dt, J = 12.6, 7.6 Hz, 2H), 1.58- 1.34 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 414.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.51 (s, 1H), 7.89-7.83 (m, 2H), 7.63 (d, J = 9.1 Hz, 2H), 4.15-4.03 (m, 4H), 3.70-3.59 (m, 4H), 3.50 (t, J = 7.0 Hz, 2H), 2.19-2.08 (m, 2H), 2.06- 1.97 (m, 2H), 1.67 (dt, J = 12.7, 7.5 Hz, 2H), 1.56-1.35 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 469.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.52 (s, 1H), 7.83-7.77 (m, 2H), 7.57 (d, J = 8.6 Hz, 2H), 4.36 (s, 2H), 4.16-3.99 (m, 3H), 3.78 (dt, J = 19.6, 4.1 Hz, 2H), 3.67- 3.58 (m, 2H), 3.50 (t, J = 7.4 Hz, 2H), 3.42-3.34 (m, 3H), 3.21 (td, J = 12.4, 3.7 Hz, 2H), 2.19-2.08 (m, 2H), 2.07-1.94 (m, 2H), 1.67 (dt, J = 12.7, 7.6 Hz, 2H), 1.58- 1.33 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 483.35 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.61 (d, J = 5.3 Hz, 2H), 8.36 (s, 1H), 7.01 (t, J = 5.3 Hz, 1H), 4.58 (d, J = 13.4 Hz, 2H), 4.29-4.18 (m, 1H), 4.10-4.00 (m, 1H), 3.69-3.60 (m, 1H), 3.51- 3.38 (m, 4H), 2.20-2.07 (m, 4H), 2.01 (d, J = 9.9 Hz, 2H), 1.84-1.70 (m, 2H), 1.70-1.59 (m, 2H), 1.53- 1.33 (m, 6H), 1.15 (d, J = 6.2 Hz, 1H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 469.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 4.43 (tt, J = 12.3, 3.6 Hz, 1H), 4.11-3.99 (m, 1H), 3.98- 3.87 (m, 1H), 3.69-3.60 (m, 1H), 3.48 (t, J = 7.0 Hz, 2H), 2.85 (s, 3H), 2.23-2.06 (m, 4H), 1.98 (t, J = 13.1 Hz, 4H), 1.72-1.60 (m, 2H), 1.54 (d, J = 11.5 Hz, 12H), 1.49-1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 461.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 4.19-4.01 (m, 3H), 3.97- 3.88 (m, 1H), 3.69-3.58 (m, 2H), 3.58-3.40 (m, 5H), 3.26-3.10 (m, 2H), 2.29- 2.16 (m, 2H), 2.16-1.93 (m, 7H), 1.72-1.58 (m, 2H), 1.51-1.34 (m, 12H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 433.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.46 (d, J = 17.7 Hz, 1H), 4.84-4.74 (m, 1H), 4.74-4.63 (m, 1H), 4.63- 4.55 (m, 2H), 4.35-4.22 (m, 2H), 4.13-4.00 (m, 1H), 3.70-3.59 (m, 1H), 3.54- 3.41 (m, 2H), 3.02 (d, J = 20.7 Hz, 3H), 2.17-2.06 (m, 2H), 2.06-1.96 (m, 2H), 1.71-1.59 (m, 2H), 1.53- 1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 377.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 4.19-4.00 (m, 2H), 3.77- 3.55 (m, 6H), 3.55-3.41 (m, 2H), 3.30-3.11 (m, 4H), 2.91 (s, 3H), 2.58-2.43 (m, 2H), 2.30-2.16 (m, 4H), 2.15-1.95 (m, 6H), 1.65 (dt, J = 14.9, 7.5 Hz, 2H), 1.53- 1.36 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 488.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 4.28-4.15 (m, 1H), 4.09- 3.97 (m, 1H), 3.69-3.60 (m, 1H), 3.51-3.40 (m, 2H), 2.17-2.06 (m, 2H), 2.05- 1.94 (m, 4H), 1.81-1.70 (m, 2H), 1.68-1.57 (m, 4H), 1.57-1.48 (m, 2H), 1.48- 1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 476.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.18 (s, 1H), 4.09-3.90 (m, 3H), 3.69- 3.60 (m, 1H), 3.50-3.38 (m, 2H), 2.18-2.04 (m, 2H), 2.04-1.86 (m, 4H), 1.77- 1.50 (m, 13H), 1.50-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 404.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.53 (s, 2H), 4.36 (s, 2H), 4.10-3.98 (m, 3H), 3.84-3.75 (m, 2H), 3.68-3.57 (m, 2H), 3.48 (t, J = 6.9 Hz, 2H), 3.36 (d, J = 12.9 Hz, 2H), 3.20 (td, J = 12.4, 3.6 Hz, 2H), 2.19-2.06 (m, 2H), 2.04-1.94 (m, 2H), 1.65 (dt, J = 12.7, 7.5 Hz, 2H), 1.43 (dd, J = 18.5, 11.2 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 497.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 4.11-3.98 (m, 2H), 3.71- 3.60 (m, 2H), 3.50-3.41 (m, 2H), 2.82-2.72 (m, 1H), 2.17-2.06 (m, 2H), 2.06- 1.95 (m, 2H), 1.64 (dt, J = 14.9, 7.5 Hz, 2H), 1.43 (dq, J = 14.7, 7.3 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H), 0.84- 0.74 (m, 2H), 0.59 (td, J = 7.0, 5.0 Hz, 2H); MS m/z 448.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 4.47-4.34 (m, 1H), 4.09- 3.97 (m, 1H), 3.70-3.58 (m, 1H), 3.53-3.40 (m, 2H), 2.38-2.24 (m, 2H), 2.17- 1.95 (m, 7H), 1.84-1.72 (m, 2H), 1.69-1.59 (m, 2H), 1.52-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 362.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 4.10-3.99 (m, 1H), 3.68- 3.59 (m, 1H), 3.57-3.43 (m, 3H), 3.27 (d, J = 6.6 Hz, 2H), 3.05-2.93 (m, 2H), 2.85 (s, 3H), 2.16-1.93 (m, 6H), 1.71-1.60 (m, 2H), 1.60-1.49 (m, 2H), 1.44 (dt, J = 15.1, 7.4 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 419.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 4.11-3.98 (m, 1H), 3.68- 3.59 (m, 3H), 3.55-3.42 (m, 3H), 3.27 (d, J = 6.5 Hz, 2H), 3.03-2.90 (m, 2H), 2.24-2.07 (m, 4H), 2.07- 1.93 (m, 5H), 1.90-1.79 (m, 2H), 1.79-1.59 (m, 7H), 1.59-1.51 (m, 2H), 1.48- 1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 473.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.25 (s, 1H), 8.20 (d, J = 2.5 Hz, 1H), 7.75- 7.69 (m, 3H), 7.47 (d, J = 8.6 Hz, 2H), 6.55-6.49 (m, 1H), 4.53 (s, 2H), 4.11-4.00 (m, 1H), 3.70-3.57 (m, 2H), 3.51-3.42 (m, 2H), 2.18- 2.05 (m, 2H), 2.05-1.95 (m, 2H), 1.71-1.59 (m, 2H), 1.52-1.35 (m, 6H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 464.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.21 (s, 1H), 7.43 (dd, J = 1.8, 0.8 Hz, 1H), 6.36 (dd, J = 3.2, 1.9 Hz, 1H), 6.30 (dd, J = 3.2, 0.6 Hz, 1H), 4.48 (s, 2H), 4.10- 4.00 (m, 1H), 3.69-3.59 (m, 1H), 3.46 (t, J = 6.8 Hz, 2H), 2.16-2.05 (m, 2H), 2.05- 1.96 (m, 2H), 1.64 (dt, J = 14.9, 7.5 Hz, 2H), 1.53-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 388.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 7.30 (dd, J = 5.1, 1.2 Hz, 1H), 7.04 (dd, J = 3.4, 1.0 Hz, 1H), 6.95 (dd, J = 5.1, 3.5 Hz, 1H), 4.65 (s, 2H), 4.11- 3.99 (m, 1H), 3.65 (td, J = 9.5, 4.2 Hz, 1H), 3.46 (t, J = 6.8 Hz, 2H), 2.19-2.06 (m, 2H), 2.06-1.95 (m, 2H), 1.64 (dt, J = 14.9, 7.5 Hz, 2H), 1.56-1.33 (m, 6H), 0.99 (t, J = 7.4 Hz,3H); MS m/z 404.20 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 8.09 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.58-7.49 (m, 3H), 7.46 (dd, J = 15.2, 7.8 Hz, 1H), 4.97 (s, 2H), 4.11- 4.00 (m, 1H), 3.70-3.60 (m, 1H), 3.51-3.41 (m, 2H), 2.17-2.07 (m, 2H), 2.07- 1.95 (m, 2H), 1.69-1.58 (m, 2H), 1.57-1.35 (m, 6H), 0.98 (t, J = 7.3 Hz, 3H); MS m/z 448.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H), 4.15-4.02 (m, 1H), 3.71-3.57 (m, 1H), 3.49 (t, J = 6.7 Hz, 2H), 2.66-2.55 (m, 2H), 2.18- 2.07 (m, 2H), 2.07-1.96 (m, 2H), 1.72-1.53 (m, 4H), 1.53-1.28 (m, 8H), 1.01 (t, J = 7.4 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); MS m/z 440.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.81 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.2 Hz, 2H), 4.80 (s, 2H), 4.44-4.34 (m, 1H), 4.14-3.85 (m, 8H), 3.79 (t, J = 7.1 Hz, 2H), 3.63-3.56 (m, 3H), 2.95 (s, 2H), 2.46-2.37 (m, 2H), 2.34-2.25 (m, 2H), 1.96 (dt, J = 15.0, 7.3 Hz, 2H), 1.84-1.65 (m, 6H), 1.29 (t, J = 7.3 Hz, 3H); MS m/z 496.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.37 (s, 1H), 7.74 (dd, J = 7.9, 1.4 Hz, 1H), 7.24-7.17 (m, 1H), 7.07 (dd, J = 8.3, 1.2 Hz, 1H), 6.96 (td, J = 7.7, 1.3 Hz, 1H), 4.14-4.02 (m, 1H), 3.89 (s, 3H), 3.69-3.60 (m, 1H), 3.50 (t, J = 7.4 Hz, 2H), 2.18-2.05 (m, 2H), 2.05- 1.94 (m, 2H), 1.72-1.62 (m, 2H), 1.55-1.32 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 414.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 7.53-7.45 (m, 2H), 6.96- 6.88 (m, 2H), 4.14-4.01 (m, 1H), 3.79 (s, 3H), 3.69-3.59 (m, 1H), 3.49 (t, J = 7.0 Hz, 2H), 2.17-2.07 (m, 2H), 2.06-1.97 (m, 2H), 1.67 (dt, J = 12.7, 7.6 Hz, 2H), 1.55- 1.35 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 414.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 7.39-7.24 (m, 5H), 4.20- 3.99 (m, 2H), 3.80-3.69 (m, 2H), 3.66-3.61 (m, 1H), 3.53-3.43 (m, 2H), 3.41- 3.33 (m, 2H), 3.22-3.15 (m, 1H), 3.15-3.07 (m, 3H), 2.30-2.17 (m, 2H), 2.15- 2.06 (m, 2H), 2.06-1.93 (m, 4H), 1.71-1.59 (m, 2H), 1.52-1.36 (m, 6H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 495.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.34-7.17 (m, 5H), 4.15- 3.98 (m, 2H), 3.70-3.59 (m, 3H), 3.53-3.42 (m, 3H), 3.18-3.04 (m, 4H), 2.73 (t, J = 7.4 Hz, 2H), 2.19 (d, J = 13.5 Hz, 2H), 2.15-2.04 (m, 5H), 2.04-1.88 (m, 4H), 1.65 (dt, J = 15.0, 7.6 Hz, 2H), 1.51-1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 509.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 9.26 (s, 1H), 9.00 (d, J = 5.1 Hz, 1H), 8.94 (d, J = 7.9 Hz, 1H), 8.30 (s, 1H), 8.21 (dd, J = 8.1, 5.8 Hz, 1H), 4.66 (s, 2H), 4.09 (d, J = 36.9 Hz, 2H), 3.77- 3.53 (m, 4H), 3.53-3.41 (m, 2H), 2.29-2.14 (m, 3H), 2.14-1.93 (m, 6H), 1.73- 1.59 (m, 2H), 1.53-1.33 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 482.35 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 4.15-4.01 (m, 1H), 3.77-3.55 (m, 2H), 3.50 (t, J = 7.1 Hz, 2H), 2.21-2.08 (m, 2H), 2.08- 1.96 (m, 2H), 1.67 (dt, J = 14.9, 7.5 Hz, 2H), 1.56-1.33 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 452.25 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.33 (s, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H), 4.55 (s, 2H), 4.11 (dd, J = 12.0, 7.0 Hz, 4H), 4.08-3.99 (m, 1H), 3.75-3.68 (m, 4H), 3.68- 3.58 (m, 1H), 3.48 (t, J = 7.0 Hz, 2H), 2.16-2.03 (m, 2H), 2.03-1.94 (m, 2H), 1.65 (dt, J = 14.9, 7.6 Hz, 2H), 1.51- 1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 483.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.50 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 4.07 (dd, J = 13.0, 3.4 Hz, 3H), 3.93- 3.83 (m, 2H), 3.70-3.62 (m, 1H), 3.58 (d, J = 13.0 Hz, 2H), 3.49 (t, J = 7.0 Hz, 2H), 3.45-3.36 (m, 2H), 3.22 (td, J = 12.3, 3.6 Hz, 2H), 3.17- 3.06 (m, 2H), 2.19-2.07 (m, 2H), 2.07-1.96 (m, 2H), 1.67 (dt, J = 12.7, 7.6 Hz, 2H), 1.55-1.35 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 497.35 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.47 (s, 1H), 7.64 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 4.15-4.04 (m, 2H), 4.03-3.72 (m, 5H), 3.72-3.58 (m, 4H), 3.58- 3.47 (m, 4H), 3.22-3.12 (m, 2H), 3.05 (s, 3H), 2.17-2.07 (m, 2H), 2.06-1.95 (m, 2H), 1.67 (dt, J = 14.9, 7.6 Hz, 2H), 1.56-1.35 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 510.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 4.15-3.98 (m, 2H), 3.79- 3.70 (m, 2H), 3.70-3.57 (m, 2H), 3.50 (dt, J = 14.5, 6.5 Hz, 2H), 3.19-3.08 (m, 2H), 3.05 (d, J = 7.3 Hz, 2H), 2.27-2.17 (m, 2H), 2.17- 2.03 (m, 3H), 2.03-1.93 (m, 3H), 1.71-1.59 (m, 2H), 1.52-1.37 (m, 6H), 1.21- 1.11 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H), 0.82-0.74 (m, 2H), 0.52-0.43 (m, 2H); MS m/z 445.35 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 4.27-4.19 (m, 1H), 4.17- 3.99 (m, 2H), 3.69-3.58 (m, 3H), 3.55-3.40 (m, 3H), 3.16-3.04 (m, 2H), 2.98 (d, J = 6.6 Hz, 2H), 2.25-1.95 (m, 8H), 1.92-1.76 (m, 5H), 1.72 (d, J = 13.2 Hz, 1H), 1.69-1.59 (m, 2H), 1.53- 1.20 (m, 9H), 1.15-1.02 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 487.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 4.27-4.21 (m, 1H), 4.16- 3.99 (m, 2H), 3.75-3.60 (m, 3H), 3.55-3.43 (m, 3H), 3.25 (d, J = 7.2 Hz, 1H), 3.17-3.05 (m, 3H), 2.40- 2.28 (m, 1H), 2.25-1.90 (m, 10H), 1.80-1.59 (m, 6H), 1.53-1.38 (m, 6H), 1.38- 1.26 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 473.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.36 (s, 1H), 4.27-4.20 (m, 1H), 4.17- 3.99 (m, 2H), 3.77-3.59 (m, 3H), 3.59-3.41 (m, 4H), 3.18-3.05 (m, 2H), 2.28- 2.06 (m, 6H), 2.05-1.91 (m, 4H), 1.90-1.59 (m, 8H), 1.52-1.34 (m, 6H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 459.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.48-7.39 (m, 4H), 7.17- 7.14 (m, 2H), 6.29-6.24 (m, 2H), 4.50 (s, 2H), 4.10-3.99 (m, 1H), 3.71-3.54 (m, 2H), 3.52-3.40 (m, 2H), 2.16- 2.06 (m, 2H), 2.05-1.96 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.54-1.33 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 463.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 9.47 (t, J = 1.5 Hz, 1H), 8.35 (s, 1H), 8.08- 8.04 (m, 1H), 7.80-7.76 (m, 1H), 7.75-7.69 (m, 2H), 7.64 (d, J = 8.7 Hz, 2H), 4.59 (s, 2H), 4.11-3.97 (m, 1H), 3.69-3.57 (m, 2H), 3.48 (t, J = 7.0 Hz, 2H), 2.17-2.05 (m, 2H), 2.05- 1.92 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.53-1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 464.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 7.54 (s, 4H), 4.52 (s, 2H), 4.10- 4.00 (m, 1H), 3.80-3.68 (m, 4H), 3.68-3.59 (m, 2H), 3.47 (t, J = 6.8 Hz, 2H), 2.33-2.22 (m, 4H), 2.16- 2.06 (m, 2H), 2.05-1.94 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.51-1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 467.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.34 (s, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 4.34 (s, 2H), 4.16-4.03 (m, 2H), 4.03-3.96 (m, 4H), 3.70- 3.59 (m, 1H), 3.59-3.43 (m, 8H), 3.15 (t, J = 11.8 Hz, 2H), 2.19 (d, J = 13.9 Hz, 2H), 2.10 (d, J = 9.1 Hz, 2H), 2.05-1.90 (m, 4H), 1.70-1.59 (m, 2H), 1.43 (dd, J = 15.0, 7.3 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 566.40 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 9.33 (d, J = 1.6 Hz, 1H), 8.34 (s, 1H), 7.78 (s, 1H), 7.67 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.6 Hz, 2H), 4.58 (s, 1H), 4.10-4.01 (m, 1H), 3.69-3.56 (m, 3H), 3.52-3.43 (m, 2H), 2.44 (s, 3H), 2.17-2.04 (m, 2H), 2.04-1.96 (m, 2H), 1.71- 1.59 (m, 2H), 1.51-1.33 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 478.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.32-8.24 (m, 1H), 7.81 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.50 (t, J =7.5 Hz, 2H), 7.45-7.38 (m, 1H), 4.59 (s, 2H), 4.11-3.97 (m, 2H), 3.70-3.56 (m, 2H), 3.54- 3.43 (m, 2H), 2.19-2.06 (m, 2H), 2.02-1.92 (m, 2H), 1.70-1.59 (m, 2H), 1.52- 1.36 (m, 6H), 0.99 (t, J = 1.4 Hz, 3H); MS m/z 540.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 7.88-7.85 (m, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.63-7.57 (m, 1H), 7.53 (d, J = 8.3 Hz, 2H), 7.50-7.46 (m, 4H), 7.44 (d, J = 8.4 Hz, 2H), 4.57 (s, 2H), 4.12-4.00 (m, 1H), 3.66-3.56 (m, 2H), 3.48 (t, J = 6.8 Hz, 2H), 2.17-1.93 (m, 4H), 1.72- 1.59 (m, 2H), 1.43 (dd, J = 18.4, 10.8 Hz, 6H), 0.99 (t, J = 7.3 Hz, 3H); MS m/z 540.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.36-8.31 (m, 1H), 7.64 (dd, J = 5.3, 3.1 Hz, 3H),7.59(d, J = 2.1 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 4.60 (s, 2H), 4.09-4.01 (m, 1H), 3.68-3.57 (m, 1H), 3.52-3.42 (m, 2H), 2.57 (s, 3H), 2.16-2.06 (m, 2H), 2.04-1.95 (m, 2H), 1.71- 1.60 (m, 2H), 1.50-1.34 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 478.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 7.15-7.09 (m, 2H), 7.03 (dd, J = 8.0, 1.9 Hz, 1H), 4.13- 3.99 (m, 1H), 3.68-3.58 (m, 1H), 3.50 (t, J = 6.8 Hz, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 2.16-2.06 (m, 2H), 2.04- 1.94 (m, 2H), 1.73-1.60 (m, 2H), 1.54-1.34 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 412.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 7.50 (d, J = 2.6 Hz, 1H), 6.98 (d, J = 9.0 Hz, 1H), 6.75 (dd, J = 9.0, 3.0 Hz, 1H), 4.15- 4.01 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.69-3.57 (m, 2H), 3.50 (t, J = 6.9 Hz, 2H), 2.17-2.06 (m, 2H), 2.05- 1.97 (m, 2H), 1.67 (dt, J = 12.6, 7.6 Hz, 2H), 1.56-1.34 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H); MS m/z 444.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 9.05 (s, 1H), 8.30 (s, 1H), 7.61 (t, J = 1.7 Hz, 1H), 7.59-7.55 (m, 1H), 7.48-7.32 (m, 4H), 5.45 (s, 2H), 4.50 (s, 2H), 4.10-4.00 (m, 1H), 3.66-3.58 (m, 2H), 3.47 (t, J = 7.0 Hz, 2H), 2.17-2.05 (m, 2H), 2.04- 1.94 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.52-1.33 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 478.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 8.75 (d, J = 0.9 Hz, 1H), 8.38-8.35 (m, 1H), 8.33 (s, 1H), 7.68-7.62 (m, 2H), 7.58 (d, J = 8.7 Hz, 2H), 4.57 (s, 2H), 4.12-3.99 (m, 1H), 3.68-3.60 (m, 2H), 3.48 (t, J = 6.9 Hz, 2H), 2.17-2.06 (m, 2H), 2.04- 1.95 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.53-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 533.30 [M + H]+.
1H NMR (400 MHz, CD3OD) δ 9.36 (d, J = 1.5 Hz, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.72-7.66 (m, 2H), 7.62 (d, J = 8.6 Hz, 2H), 4.73 (d, J = 0.6 Hz, 2H), 4.59 (s, 2H), 4.11-4.00 (m, 1H), 3.70-3.57 (m, 1H), 3.48 (t, J = 7.0 Hz, 2H), 2.17-2.05 (m, 2H), 2.05- 1.93 (m, 2H), 1.65 (dt, J = 12.7, 7.6 Hz, 2H), 1.51-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 494.30 [M + H]+.
A solution of 2-chloropyridine-5-sulfonyl chloride (212 mg, 1.0 mmol) in DCM (10 mL) was added morpholine (87.1 mg, 1.0 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 10 min and then DIEA (194 mg, 1.5 mmol) was added dropwisely. The mixture was stirred at 0° C. for 2 h. Then the mixture was diluted with EtOAc (15 mL) and washed with water (2×). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO to give the title compound as a white solid (246.1 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 8.73-8.65 (m, 1H), 7.94 (dd, J=8.3, 2.5 Hz, 1H), 7.49 (dd, J=8.3, 0.6 Hz, 1H), 3.74-3.63 (m, 4H), 2.99 (dd, J=5.6, 3.9 Hz, 4H); 13C NMR (101 MHz, cdcl3) δ 155.9, 148.7, 137.9, 131.1, 124.9, 65.9, 45.8; MS m/z 263.30 [M+H]+.
A 10 mL microwave tube was charged with 2,4-dichloropyrimidine-5-boronic acid pinacol ester (55 mg, 0.20 mmol), K2CO3 (41.5 mg, 0.30 mmol) and THF (2.0 mL). The resulting mixture was then heated to 80° C. for 15 min under Microwave irradiation. Then 4-((6-chloropyridin-3-yl)sulfonyl)morpholine (52.5 mg, 0.20 mmol), Pd(PPh3)4 (23.1 mg, 0.02 mmol), K2CO3 (41.5 mg, 0.30 mmol), butylamine (116.8 mg, 1.60 mmol) and water (0.5 mL) were added sequentially. The resulting mixture was heated to 150° C. for 30 min under Microwave irradiation. The mixture was diluted with EtOAc (15 mL) and washed with water (2×). The organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified on ISCO and HPLC to give the title compound as a white solid (27.4 mg, 28%) and (1r,4r)-4-((2-(butylamino)pyrimidin-4-yl)amino)cyclohexanol (25.7 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 10.65 (d, J=7.1 Hz, 1H), 9.46 (t, J=5.4 Hz, 1H), 8.87 (d, J=2.2 Hz, 1H), 8.31 (s, 1H), 8.10 (dd, J=8.6, 2.3 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 4.19-4.09 (m, 1H), 3.84-3.68 (m, 5H), 3.51-3.44 (m, 2H), 3.15-3.06 (m, 4H), 2.86-2.66 (m, 3H), 2.28-2.15 (m, 2H), 2.13-2.01 (m, 2H), 1.72-1.61 (m, 2H), 1.56-1.36 (m, 6H), 0.96 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.4, 156.9, 153.1, 146.6, 142.8, 136.8, 130.2, 118.9, 103.4, 69.2, 66.0, 49.7, 45.8, 41.3, 33.3, 31.0, 29.5, 20.1, 13.7; MS m/z 491.30 [M+H]+.
1H NMR (400 MHz, CDCl3) δ 10.74 (d, J = 7.2 Hz, 1H), 9.09 (t, J = 5.4 Hz, 1H), 8.97 (d, J = 2.0 Hz, 1H), 8.47 (d, J = 11.7 Hz, 1H), 8.25-8.14 (m, 1H), 7.83 (t, J = 7.1 Hz, 1H), 5.27- 5.16 (m, 1H), 4,19-4.03 (m, 4H), 3.82-3.75 (m, 1H), 3.52- 3.42 (m, 2H), 2.90 (t, J = 5.5 Hz, 2H), 2.66 (t, J = 12.7 Hz, 2H), 2.29-2.00 (m, 4H), 1.72- 1.60 (m, 5H), 1.52-1.37 (m, 12H), 1.16-1.03 (m, 2H), 0.97 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 159.5, 156.4, 154.8, 152.9, 145.9, 142.7, 136.1, 134.7, 119.3, 103.7, 79.9, 69.2, 49.7, 48.6, 41.3, 36.6, 33.2, 31.0, 29.5, 28.4, 20.1, 13.7; MS m/z 618.40 [M + H]+.
1H NMR (400 MHz, CD3OD + CDCl3) δ 8.89 (t, J = 2.4 Hz, 1H), 8.39 (d, J = 17.0 Hz, 1H), 8.19-8.11 (m, 1H), 7.88 (t, J = 8.7 Hz, 1H), 5.08-4.93 (m, 1H), 4.25-4.11 (m, 1H), 4.12- 3.97 (m, 1H), 3.70-3.56 (m, 1H), 3.46-3.38 (m, 2H), 3.38- 3.34 (m, 1H), 2.87-2.74 (m, 4H), 2.25-2.18 (m, 1H), 2.17- 2.08 (m, 2H), 2.03-1.95 (m, 3H), 1.93-1.85 (m, 2H), 1.79- 1.68 (m, 2H), 1.64-1.56 (m, 3H), 1.48-1.33 (m, 6H), 0.92 (td, J = 7.4, 2.1 Hz, 3H); MS m/z 518.30 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.95 (d, J = 7.2 Hz, 1H), 9.03-8,85 (m, 2H), 8.33 (d, J = 14.4 Hz, 1H), 8.12 (dd, J = 8.6, 2.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 6.17 (d, J = 7.9 Hz, 1H), 4.24-3.70 (m, 9H), 3.51-3.40 (m, 2H), 2.92 (t, J = 12.1 Hz, 2H), 2.26-2.14 (m, 2H), 2.06 (t, J = 10.6 Hz, 4H), 1.70-1.59 (m, 2H), 1.54-1.35 (m, 14H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 164.0, 159.6, 155.3, 154.8, 152.9, 146.6, 141.6, 135.9, 128.0, 118.6, 104.1, 80.1, 69.2, 49.6, 47.7, 41.3, 33.2, 32.0, 31.0, 29.4, 28.4, 20.0, 13.7; MS m/z 568.40 [M + H]+.
1H NMR (400 MHz, CDCl3) δ 10.67 (s, 1H), 8.50 (d, J = 4.7 Hz, 1H), 8.12 (s, 1H), 7.79- 7.70 (m, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.24-7.14 (m, 1H), 4.13-4.04 (m, 1H), 3.79-3.71 (m, 1H), 3.48-3.38 (m, 2H), 2.26-2.13 (m, 2H), 2.11-2.01 (m, 2H), 1.69-1.60 (m, 2H), 1.54-1.34 (m, 6H), 0.95 (t, J = 7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 163.8, 159.9, 147.2, 137.5, 131.6, 118.9, 115.1, 104.4, 69.5, 49.6, 41.2, 33.6, 31.4, 29.8, 20.1, 13.8; MS m/z 342.25 [M + H]+.
A solution of 5-bromo-2,4-dichloropyrimidine (34.2 g, 150 mmol) and 4-aminocyclohexanol (17.3 g, 150 mmol) in i-PrOH (300 mL) was added DIPEA (39.2 mL, 225 mmol). The reaction mixture was stirred for 12 h. Then the solvent was evaporated under reduced pressure and the residue was then redissolved in EtOAc and washed with brine. The organic layer was dried (Na2SO4) and concentrated to yield 4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexanol (46 g, 150 mmol) which was used without further purification.
To a solution of 4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexanol (46 g, 150 mmol) in toluene (150 mL) was added n-butylamine (150 mL, 1.5 mol). The reaction mixture was heated at 80° C. for 12 h. Then the solvent was evaporated under reduced pressure and the residue was then redissolved in EtOAc and washed with brine. The organic layer was dried (Na2SO4) and concentrated to yield trans-4-((5-bromo-2-(butylamino)pyrimidin-4-yl)amino)cyclohexanol (47.5 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 5.01-4.80 (m, 2H), 3.97-3.82 (m, 1H), 3.65 (tt, J=10.4, 4.2 Hz, 1H), 3.31 (dt, J=7.1, 6.1 Hz, 2H), 2.21 (s, 1H), 2.16-2.06 (m, 2H), 2.06-1.95 (m, 2H), 1.59-1.49 (m, 2H), 1.49-1.34 (m, 4H), 1.34-1.20 (m, 2H), 0.92 (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 161.14 (s), 157.59 (s), 155.72 (s), 69.70 (s), 48.85 (s), 41.39 (s), 33.94 (s), 31.84 (s), 30.62 (s), 20.12 (s), 13.86 (s). MS m/z 343.0 [M+1]+;
A mixture of lithium (5-fluoropyridin-2-yl)trihydroxyborate (99 mg, 0.60 mmol), copper bromide (3.0 mg, 0.020 mmol), potassium carbonate (83.0 mg, 0.60 mmol), 4-((5-bromo-2-(butylamino)pyrimidin-4-yl)amino)cyclohexanol (68.7 mg, 0.20 mmol) and PdCl2(dppf) (8.2 mg, 0.010 mmol) in a mixture of DMF and H2O (2.0 mL/0.5 mL) was heated at 120° C. in the open air for 30 min, and then allowed to cool to room temperature. The insoluble material was removed by filtration through a short pad of celite, which was washed with DMF. The solvent was then removed under reduced pressure and the residue was Purified on ISCO to provide trans-4-((2-(butylamino)-5-(5-fluoropyridin-2-yl)pyrimidin-4-yl)amino)cyclohexanol (UNC2861A) (46 mg, 65%). 1H NMR (400 MHz, CD3OD) δ 8.54 (d, J=3.0 Hz, 1H), 8.26 (s, 1H), 7.93 (dd, J=9.0, 4.1 Hz, 1H), 7.80-7.71 (m, 1H), 4.20-4.05 (m, 1H), 3.67 (td, J=10.0, 5.1 Hz, 1H), 3.48 (s, 2H), 2.16 (d, J=8.5 Hz, 2H), 2.05-1.92 (m, 2H), 1.67 (dt, J=12.6, 7.5 Hz, 2H), 1.59-1.38 (m, 6H), 1.00 (t, J=7.4 Hz, 3H). LC-MS (ESI+): tR=4.481 min, MS m/z 360.0 [M+1]+.
A mixture of palladium(II) acetate (2.9 mg, 0.013 mmol), potassium phosphate (186.8 mg, 0.88 mmol), trans-4-((5-bromo-2-(butylamino)pyrimidin-4-yl)amino)cyclohexanol (150 mg, 0.44 mmol), SPhos (9.1 mg, 0.022 mmol) and (5-formylfuran-2-yl)boronic acid (92.3 mg, 0.66 mmol) in butanol (2.5 mL) was degassed and heated under N2 atmosphere and microwave irradiation at 150° C. in a 10 ml microwave tube for 20 min. The resulting mixture was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified on HPLC to provide 5-(2-(butylamino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidin-5-yl)furan-2-carbaldehyde (50.1 mg, 32%). 1H NMR (400 MHz, cdcl3) δ 9.49 (s, 1H), 8.22 (s, 1H), 7.28 (d, J=3.8 Hz, 1H), 6.55 (d, J=3.8 Hz, 1H), 5.25-5.07 (m, 1H), 4.13-3.98 (m, 1H), 3.79-3.70 (m, 1H), 3.41 (dd, J=13.3, 6.9 Hz, 2H), 2.25-2.15 (m, 2H), 2.10-2.01 (m, 2H), 1.79-1.68 (m, 1H), 1.65-1.55 (m, 2H), 1.54-1.34 (m, 5H), 0.95 (t, J=7.3 Hz, 3H); 13C NMR (101 MHz, cdcl3) δ 175.1, 161.9, 158.9, 157.7, 156.1, 150.4, 125.0, 104.4, 69.6, 48.6, 41.2, 33.6, 31.9, 30.2, 20.1, 13.9; MS m/z 359.20 [M+H]+.
A mixture of 1-methylpiperazine (29.3 mg, 0.29 mmol), 5-(2-(butylamino)-4-((trans-4-hydroxycyclohexyl)amino)pyrimidin-5-yl)furan-2-carbaldehyde (35 mg, 0.098 mmol), acetic acid (28 mg, 0.29 mmol) and sodium triacetoxyborohydride (62.1 mg, 0.29 mmol) in DCM (10 mL) was stirred at room temperature for 2 h, then quenched with NaHCO3 (sat.) and extracted with DCM (3×). The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated. The residue was purified on HPLC to provide trans-4-((2-(butylamino)-5-(5-((4-methylpiperazin-1-yl)methyl)furan-2-yl)pyrimidin-4-yl)amino)cyclohexanol (UNC2897A) (35.2 mg, 82%). 1H NMR (400 MHz, cd3od) δ 7.82 (s, 1H), 6.68 (d, J=3.4 Hz, 1H), 6.59 (d, J=3.4 Hz, 1H), 4.18-4.09 (m, 1H), 3.99 (s, 2H), 3.64-3.54 (m, 1H), 3.54-3.42 (m, 2H), 3.45-3.32 (m, 4H), 3.18-2.94 (m, 4H), 2.90 (s, 3H), 2.19-1.97 (m, 4H), 1.71-1.62 (m, 2H), 1.59-1.31 (m, 6H), 1.00 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, cd3od) δ 160.6, 160.2, 149.5, 146.2, 139.4, 117.5, 114.6, 112.7, 109.6, 68.7, 52.5, 48.8, 42.0, 40.8, 33.3, 30.9, 29.0, 19.7, 12.7; MS m/z 443.35 [M+H]+.
1H NMR (400 MHz, CD3OD) δ 8.54 (dd, J = 5.5, 0.5 Hz, 1H), 8.38 (s, 1H), 8.02 (d, J = 1.5 Hz, 1H), 7.46 (dd, J = 5.5, 1.8 Hz, 1H), 4.23-4.05 (m, 1H), 3.72-3.59 (m, 1H), 3.49 (d, J = 7.7 Hz, 2H), 2.16 (d, J = 10.3 Hz, 2H), 2.02 (dd, J = 10.0, 3.7 Hz, 2H), 1.67 (tt, J = 8.1, 6.7 Hz, 2H), 1.59-1.36 (m, 5H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 376.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 9.14 (d, J = 1.2 Hz, 1H), 8.62 (dd, J = 2.6, 1.6 Hz, 1H), 8.59 (d, J = 2.6 Hz, 1H), 4.28- 4.10 (m, 1H), 3.66 (ddd, J = 13.8, 9.8, 3.9 Hz, 1H), 3.51 (s, 2H), 2.16 (d, J = 10.0 Hz, 2H), 2.02 (d, J = 12.3 Hz, 2H), 1.68 (dt, J = 12.7, 7.6 Hz, 2H), 1.61-1.35 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H). MS m/z 343.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.55 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.99 (dd, J = 8.6, 2.7 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1H), 7.82 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.63 (ddd, J = 8.1, 7.0, 1.1 Hz, 1H), 4.28- 4.11 (m, 1H), 3.83-3.66 (m, 1H), 3.50 (d, J = 16.0 Hz, 2H), 2.30 (d, J = 9.6 Hz, 2H), 2.09 (d, J = 9.7 Hz, 2H), 1.77-1.59 (m, 4H), 1.59-1.40 (m, 4H), 1.02 (t, J = 7.4 Hz, 3H). MS m/z 392.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 7.75 (s, 1H), 7.37-7.24 (m, 5H), 4.79 (s, 2H), 4.59 (s, 2H), 4.13 (s, 1H), 3.74-3.62 (m, 1H), 3.53 (d, J = 30.8 Hz, 2H), 2.16 (d, J = 7.7 Hz, 2H), 2.02 (d, J = 12.3 Hz, 2H), 1.74-1.61 (m, 2H), 1.59- 1.36 (m, 6H), 1.00 (t, J = 7.3 Hz, 3H). MS m/z 468.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.78 (d, J = 1.8 Hz, 1H), 8.45 (s, 1H), 8.15 (dd, J = 8.5, 2.3 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 4.48 (s, 2H), 4.22- 4.13 (m, 1H), 4.05 (s, 2H), 3.81 (s, 2H), 3.66 (dd, J = 10.0, 4.9 Hz, 1H), 3.46 (d, J = 34.9 Hz, 4H), 3.26-3.17 (m, 2H), 2.18 (d, J = 11.2 Hz, 2H), 2.08-1.97 (m, 2H), 1.68 (dd, J = 8.2, 6.0 Hz, 2H), 1.59-1.39 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CD3OD) δ 173.60 (s), 159.49 (s), 154.02 (s), 149.84 (s), 141.27 (s), 140.70 (s), 125.88 (s), 123.30 (s), 120.06 (s), 68.45 (s), 63.48 (s), 57.10 (s), 51.52 (s), 49.93 (s), 40.86 (s), 32.85 (s), 30.74 (s), 29.19 (s), 19.68 (s), 12.72 (s). MS m/z 441.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 1.8 Hz, 1H), 8.41 (s, 1H), 8.09 (dd, J = 8.5, 2.3 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 4.32 (s, 2H), 4.22- 4.05 (m, 1H), 3.74-3.61 (m, 1H), 3.47 (m, 2H), 3.22-3.13 (m, 1H), 2.18 (dd, J = 23.9, 11.4 Hz, 4H), 2.00 (dd, J = 13.3, 6.8 Hz, 2H), 1.90 (d, J = 12.6 Hz, 2H), 1.67 (m, 4H), 1.56-1.31 (m, 8H), 1.32-1.19 (m, 2H), 1.04-0.92 (t, J = 4 Hz, 3H). MS m/z 453.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.78 (d, J = 2.0 Hz, 1H), 8.43 (s, 1H), 8.16 (dd, J = 8.5, 2.3 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 4.50 (s, 2H), 4.19- 4.10 (m, 1H), 3.75-3.69 (m, 1H), 3.68-3.62 (m, 2H), 3.57- 3.41 (m, 4H), 2.47-2.34 (m, 4H), 2.15 (d, J = 12.5 Hz, 2H), 2.05-1.96 (m, 2H), 1.70-1.60 (m, 2H), 1.46 (ddd, J = 15.6, 14.9, 7.4 Hz, 6H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 475.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.54 (d, J = 2.9 Hz, 1H), 8.27 (s, 1H), 7.93 (dd, J = 9.0, 4.1 Hz, 1H), 7.75 (td, J = 8.7, 2.9 Hz, 1H), 3.56 (d, J = 6.5 Hz, 2H), 3.48 (s, 2H), 3.11- 3.01 (m, 1H), 2.08 (d, J = 10.5 Hz, 2H), 1.95 (d, J = 12.4 Hz, 2H), 1.77 (s, 1H), 1.65 (dt, J = 14.9, 7.4 Hz, 2H), 1.42 (qd, J = 14.5, 5.2 Hz, 4H), 1.29- 1.13 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 373.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.87 (s, 1H), 8.45 (s, 1H), 8.25 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 4.62 (s, 2H), 4.22-4.07 (m, 1H), 3.91 (m, 3H), 3.71-3.44 (m, 8H), 2.98 (s, 3H), 2.38 (s, 2H), 2.14 (d, J = 9.9 Hz, 2H), 2.01 (d, J = 12.9 Hz, 2H), 1.65 (m, 2H), 1.48 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 468.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 8.43 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 8.01 (d, J = 8.3 Hz, 1H), 4.50 (s, 2H), 4.20-4.10 (m, 1H), 3.66 (ddd, J = 12.4, 10.8, 7.5 Hz, 1H), 3.61-3.41 (m, 4H), 3.17 (dd, J = 42.2, 4.4 Hz, 2H), 2.25-2.10 (m, 4H), 2.01 (d, J = 11.8 Hz, 4H), 1.71-1.58 (m, 2H), 1.58-1.36 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 425.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 1.9 Hz, 1H), 8.43 (s, 1H), 8.08 (dd, J = 8.5, 2.3 Hz, 1H), 8.00 (d, J = 8.5 Hz, 1H), 4.20 (s, 2H), 4.18- 4.11 (m, 1H), 3.90-3.80 (m, 1H), 3.70-3.62 (m, 1H), 3.49 (s, 2H), 2.40-2.31 (m, 2H), 2.30-2.23 (m, 2H), 2.16 (d, J = 11.0 Hz, 2H), 2.04-1.98 (m, 2H), 1.96-1.86 (m, 2H), 1.66 (dt, J = 12.6, 7.6 Hz, 2H), 1.55-1.39 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 425.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 9.11 (s, 1H), 8.69 (s, 1H), 8.23 (d, J = 26.9 Hz, 2H), 4.62 (s, 2H), 4.13 (s, 1H), 3.71- 3.43 (m, 3H), 2.94 (s, 1H), 2.22-1.89 (m, 4H), 1.67 (s, 2H), 1.59-1.31 (m, 6H), 1.11 (s, 2H), 0.98 (t, J = 6.9 Hz, 5H). MS m/z 411.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 9.13 (s, 1H), 8.73 (s, 1H), 8.23 (s, 2H),4.53 (s, 2H), 4.13 (s, 1H), 3.73 (dd, J = 10.9, 5.3 Hz, 1H), 3.68-3.46 (m, 3H), 2.21 (s, 2H), 2.14-1.94 (m, 4H), 1.87 (s, 4H), 1.64 (d, J = 34.4 Hz, 4H), 1.59-1.29 (m, 6H), 0.98 (t, J = 6.9 Hz, 3H). MS m/z 439.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.76 (d, J = 1.9 Hz, 1H), 8.42 (s, 1H), 8.13 (dd, J = 8.5, 2.3 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 4.32 (d, J = 7.5 Hz, 2H), 4.15 (ddd, J = 14.4, 9.0, 3.8 Hz, 1H), 3.69-3.59 (m, 1H), 3.56-3.41 (m, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.16 (d, J =10.8 Hz, 2H), 2.08-1.95 (m,2H), 1.66 (dt, J = 12.6, 7.6 Hz, 2H), 1.58-1.36 (m, 6H), 1.20-1.11 (m, 1H), 0.98 (td, J = 7.4, 2.8 Hz, 3H), 0.78-0.62 (m, 2H), 0.43 (tt, J = 14.6, 7.3 Hz, 2H). MS m/z 425.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.75 (d, J = 1.5 Hz, 1H), 8.44 (s, 1H), 8.16-8.07 (m, 1H), 8.03 (d, J = 8.5 Hz, 1H), 4.43 (s, 2H), 4.15 (dd, J = 12.3, 8.4 Hz, 1H), 3.69-3.62 (m, 1H), 3.48 (d, J = 10.6 Hz, 2H), 2.90 (s, 6H), 2.16 (d, J = 10.2 Hz,2H), 2.01 (d, J = 11.0 Hz, 2H), 1.72-1.61 (m, 2H), 1.56-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 399.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.73 (d, J = 1.8 Hz, 1H), 8.43 (s, 1H), 8.15-8.04 (m, 1H), 8.00 (d, J = 8.5 Hz, 1H), 4.30 (s, 2H), 4.15 (ddd, J = 14.3, 9.0, 3.8 Hz, 1H), 3.72- 3.61 (m, 1H), 3.47 (d, J = 10.5 Hz, 2H), 3.20-3.11 (m, 2H), 2.16 (d, J = 10.9 Hz, 2H), 2.01 (dd, J = 9.9, 3.8 Hz, 2H), 1.72-1.59 (m, 2H), 1.55-1.40 (m, 6H), 1.36 (t, J = 7.3 Hz, 3H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 399.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.75 (d, J = 1.9 Hz, 1H), 8.42 (s, 1H), 8.13 (dd, J = 8.5, 2.3 Hz, 1H), 8.01 (d, J = 8.5 Hz, 1H), 4.36 (s, 2H), 4.20- 4.08 (m, 1H), 3.89-3.80 (m, 2H), 3.66 (d, J = 4.0 Hz, 1H), 3.49 (s, 2H), 3.23-3.14 (m, 2H), 2.16 (d, J = 10.6 Hz, 2H), 2.07-1.92 (m, 2H), 1.66 (dt, J = 12.6, 7.6 Hz, 2H), 1.59-1.32 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 415.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 9.01-8.91 (m, 2H), 8.44- 8.31 (m, 3H), 8.06 (t, J = 10.8 Hz, 1H), 7.27-7.04 (m, 2H), 4.76 (s, 2H), 4.65-4.53 (m, 2H), 4.17-4.11 (m, 1H), 3.72- 3.58 (m, 2H), 3.56-3.47 (m, 1H), 2.13 (d, J = 10.4 Hz, 2H), 2.01 (d, J = 7.4 Hz, 2H), 1.66 (dt, J = 12.6, 7.6 Hz, 2H), 1.59-1.36 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 462.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.91 (s, 1H), 8.43-8.28 (m, 2H), 8.07 (d, J = 8.4 Hz, 1H), 7.65-7.55 (m, 2H), 7.50-7.38 (m, 3H), 4.48 (s, 2H), 4.37 (s, 2H), 4.16-4.05 (m, 1H), 3.63 (ddd, J = 21.0, 15.6, 14.7 Hz, 1H), 3.55-3.43 (m, 2H), 2.11 (d, J = 11.8 Hz, 2H), 2.00 (d, J = 10.4 Hz, 2H), 1.71-1.61 (m, 2H), 1.46 (ddd, J = 22.3, 18.0, 9.7 Hz, 6H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 461.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 8.10-7.98 (m, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 1.4 Hz, 1H), 4.52 (s, 2H), 4.14 (tt, J = 11.2, 3.9 Hz, 1H), 3.66 (ddd, J = 14.6, 10.4, 4.2 Hz, 1H), 3.48 (dd, J = 7.9, 6.2 Hz, 2H), 2.94-2.83 (m, 1H), 2.20 (d, J = 10.8 Hz, 2H), 2.05 (d, J = 10.4 Hz, 2H), 1.69 (dd, J = 12.2, 4.8 Hz, 2H), 1.51 (ddd, J = 22.6, 19.3, 9.9 Hz, 6H), 1.01 (t, J = 7.4 Hz, 3H), 0.98-0.91 (m, 4H). MS m/z 411.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.32 (s, 1H), 8.07 (t, J = 7.9 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.78 (d, J = 7.5 Hz, 1H), 4.63 (s, 2H), 4.12 (dd, J = 9.6, 5.7 Hz, 1H), 3.88-3.62 (m, 9H), 3.50 (s, 2H), 3.00 (s, 3H), 2.17 (d, J = 10.7 Hz, 2H), 2.06 (d, J = 10.4 Hz, 2H), 1.68 (dt, J = 14.9, 7.5 Hz, 4H), 1.44 (dt, J = 21.9, 11.0 Hz, 4H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 454.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.77 (d, J = 1.9 Hz, 1H), 8.45 (s, 1H), 8.14 (dd, J = 8.5, 2.2 Hz, 1H), 8.03 (d, J = 8.5 Hz, 1H), 4.42 (s, 2H), 4.19- 4.11 (m, 1H), 3.71-3.61 (m, 1H), 3.50 (d, J = 11.7 Hz, 4H), 3.03 (td, J = 12.3, 2.5 Hz, 2H), 2.17 (d, J = 10.9 Hz, 2H), 1.99 (m, 5H), 1.89-1.74 (m, 3H), 1.72-1.59 (m, 2H), 1.59-1.39 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 439.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 1.7 Hz, 1H), 8.39 (s, 1H), 8.12 (dd, J = 8.5, 2.1 Hz, 1H), 7.97 (d, J = 8.5 Hz, 1H), 4.31-4.19 (m, 2H), 4.16 (ddd, J = 14.4, 9.0, 3.9 Hz, 1H), 3.74-3.38 (m, 9H), 3.28-3.11 (m, 2H), 2.97 (s, 3H), 2.17 (d, J = 10.6 Hz, 2H), 2.10-1.95 (m, 2H), 1.67 (dt, J = 12.6, 7.6 Hz, 2H), 1.59-1.36 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H). MS m/z 454.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.30 (s, 1H), 8.07 (t, J = 1.9 Hz, 1H), 7.93 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 7.5 Hz, 1H), 4.56 (s, 2H), 4.15 (td, J = 7.5, 3.7 Hz, 1H), 3.96 (d, J = 59.6 Hz, 4H), 3.71-3.62 (m, 1H), 3.51 (s, 6H), 2.17 (d, J = 10.8 Hz, 2H), 2.05 (d, J = 10.5 Hz, 2H), 1.66 (dt, J = 22.6, 11.0 Hz, 4H), 1.50-1.36 (m, 4H), 1.01 (t, J = 7.4 Hz, 3H). MS m/z 441.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.61 (s, 1H), 8.22 (d, J = 7.4 Hz, 1H), 7.98-7.88 (m, 2H), 4.27 (d, J = 13.6 Hz; 2H), 4.13 (s, 1H), 3.80-3.64 (m, 3H), 3.62-3.49 (m, 4H), 3.42 (d, J = 11.5 Hz, 2H), 2.01 (s, 3H), 1.68 (dt, J = 14.6, 7.3 Hz, 2H), 1.59-1.25 (m, 6H), 1.00 (t, J = 7.3 Hz, 3H). MS m/z 440.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 9.02 (d, J = 2.2 Hz, 1H), 8.43 (s, 1H), 8.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.99 (d, J = 8.5 Hz, 1H), 4.22-4.11 (m, 2H), 3.98 (d, J = 6.8 Hz, 1H), 3.72- 3.62 (m, 2H), 3.58 (dd, J = 15.5, 6.3 Hz, 2H), 3.53-3.41 (m, 2H), 3.18 (dd, J = 13.3, 10.6 Hz, 2H), 2.88 (s, 3H), 2.26 (d, J = 14.9 Hz, 2H), 2.17 (d, J = 11.8 Hz, 2H), 2.01 (d, J = 14.1 Hz, 2H), 1.93 (dd, J = 12.2, 3.3 Hz, 2H), 1.71-1.58 (m, 2H), 1.59-1.40 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 482.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 2.0 Hz, 1H), 8.42 (d, J = 2.3 Hz, 1H), 8.03 (dt, J = 15.3, 5.3 Hz, 2H), 4.22-4.10 (m, 1H), 3.95 (s, 1H), 3.71-3.41 (m, 8H), 3.26- 3.17 (m, 2H), 2.95 (s, 3H), 2.16 (d, J = 10.4 Hz, 2H), 2.01 (d, J = 10.6 Hz, 2H), 1.66 (dt, J = 14.9, 7.4 Hz, 2H), 1.61- 1.32 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 468.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.43 (s, 1H), 8.00 (s, 2H), 4.64 (s, 1H), 4.20-4.11 (m, 1H), 3.74-3.43 (m, 6H), 3.23 (s, 1H), 3.00 (d, J = 14.4 Hz, 3H), 2.90 (s, 3H), 2.32-1.97 (m, 8H), 1.68 (dt, J = 14.9, 7.6 Hz, 2H), 1.59-1.36 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H). MS m/z 496.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.71-8.57 (m, 1H), 8.33 (s, 1H), 7.96 (dd, J = 8.8, 2.5 Hz, 1H), 7.89 (d, J = 8.8 Hz, 1H), 4.22-4.05 (m, 1H), 3.77-3.61 (m, 1H), 3.49 (s, 2H), 2.16 (d, J = 10.6 Hz, 2H), 2.08-1.95 (m, 2H), 1.67 (dt, J = 12.7, 7.6 Hz, 2H), 1.59-1.33 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 376.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.71 (s, 1H), 8.29 (s, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.3 Hz, 1H), 4.14 (td, J = 10.5, 5.4 Hz, 1H), 3.99- 3.58 (m, 12H), 3.50 (s, 2H), 3.38-3.31 (m, 1H), 3.04 (s, 3H), 2.13 (d, J = 10.2 Hz, 2H), 2.01 (d, J = 10.5 Hz, 2H), 1.67 (dt, J = 14.9, 7.5 Hz, 2H), 1.61-1.35 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 468.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 1.6 Hz, 1H), 8.38 (s, 1H), 8.09-7.95 (m, 1H), 7.91 (d, J = 8.5 Hz, 1H), 4.15 (td, J = 10.4, 5.3 Hz, 1H), 4.04 (s, 2H), 3.77-3.37 (m, 9H), 3.25-3.07 (m, 3H), 2.96 (s, 3H), 2.17 (d, J = 10.2 Hz, 2H), 2.07-1.97 (m, 2H), 1.67 (dt, J = 12.7, 7.6 Hz, 2H), 1.62-1.36 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 478.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.63 (d, J = 1.5 Hz, 1H), 8.26 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.4 Hz, 1H), 4.19-4.11 (m, 1H), 4.05- 3.41 (m, 11H), 3.41-3.34 (m, 2H), 3.02 (s, 3H), 2.88 (t, J = 7.6 Hz, 2H), 2.29-2.20 (m, 2H), 2.19-2.08 (m, 2H), 2.07- 1.98 (m, 2H), 1.71-1.61 (m, 2H), 1.61-1.36 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 482.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.90 (d, J = 2.5 Hz, 1H), 8.26 (s, 1H), 8.19 (dd, J = 8.9, 2.5 Hz, 1H), 7.87 (d, J = 8.9 Hz, 1H), 4.14 (dd, J = 12.4, 8.5 Hz, 1H), 3.65 (ddd, J = 21.9, 14.7, 6.2 Hz, 2H), 3.52- 3.40 (m, 2H), 3.12 (dd, J = 13.1, 10.5 Hz, 2H), 2.91 (s, 3H), 2.80-2.72 (m, 1H), 2.18 (t, J = 14.9 Hz, 4H), 2.03 (d, J = 11.5 Hz, 4H), 1.75-1.59 (m, 2H), 1.58-1.36 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 482.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 8.06 (d, J = 2.7 Hz, 1H), 7.98 (s, 1H), 7.83 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 4.13 (dt, J = 10.5, 8.6 Hz, 1H), 3.74-3.56 (m, 1H), 3.48 (d, J = 1.6 Hz, 2H), 2.19-1.95 (m, 7H), 1.74-1.62 (m, 2H), 1.61-1.38 (m, 6H), 1.00 (dt, J = 7.8, 6.9 Hz, 3H). MS m/z 399.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.80 (d, J = 2.2 Hz, 1H), 8.21 (s, 1H), 8.08 (dd, J = 8.9, 2.6 Hz, 1H), 7.78 (d, J = 8.9 Hz, 1H), 4.14-4.02 (m, 1H), 3.74-3.56 (m, 1H), 3.45 (s, 2H), 2.16 (d, J = 11.4 Hz, 2H), 2.07-1.95 (m, 2H), 1.86-1.74 (m, 1H), 1.72-1.59 (m, 2H), 1.46 (ddd, J = 14.9, 10.9, 8.3 Hz, 6H), 1.04-0.84 (m, 7H). MS m/z 425.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.16 (dd, J = 8.9, 2.6 Hz, 1H), 8.04-7.96 (m, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 4.13 (dd, J = 10.0, 4.0 Hz, 2H), 3.66 (dd, J = 13.7, 4.5 Hz, 2H), 3.47 (d, J = 1.6 Hz, 3H), 2.44-1.88 (m, 11H), 1.75-1.58 (m, 3H), 1.56-1.36 (m, 6H), 1.00 (td, J = 7.3, 1.1 Hz, 4H). MS m/z 439.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.82 (d, J = 2.2 Hz, 1H), 8.24-8.15 (m, 1H),7.83 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.14 (dd, J = 9.1, 5.3 Hz, 1H), 3.77-3.59 (m, 1H), 3.47 (d, J = 1.5 Hz, 2H), 2.85 (dd, J = 15.8, 7.8 Hz, 1H), 2.16 (s, 2H), 2.08-1.91 (m, 4H), 1.89-1.72 (m, 4H), 1.72- 1.59 (m, 4H), 1.61-1.36 (m, 6H), 1.00 (dd, J = 8.3, 6.5 Hz, 3H). MS m/z 453.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.99 (d, J = 2.1 Hz, 1H), 8.32 (dd, J = 8.9, 2.6 Hz, 1H), 8.28 (s, 1H), 8.03-7.94 (m, 2H), 7.90 (d, J = 8.9 Hz, 1H), 7.62 (ddd, J = 6.6, 3.8, 1.3 Hz, 1H), 7.58-7.51 (m, 2H), 4.20- 4.10 (m, 1H), 3.68 (td, J = 10.1, 4.9 Hz, 1H), 3.48 (d, J = 1.7 Hz, 2H), 2.19 (d, J = 10.5 Hz, 2H), 2.03 (d, J = 11.4 Hz, 2H), 1.68 (dt, J = 12.7, 7.6 Hz, 2H), 1.61-1.38 (m, 6H), 1.01 (t, J = 9.7 Hz, 3H). MS m/z 461.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.86-8.74 (m, 1H), 8.23 (s, 1H), 8.15 (dd, J = 8.9, 2.6 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 4.14 (td, J = 10.7, 5.4 Hz, 1H), 3.77-3.61 (m, 1H), 3.56-3.41 (m, 2H), 2.41 (ddd, J = 11.8, 7.7, 3.4 Hz, 1H), 2.16 (d, J = 12.3 Hz, 2H), 2.02 (d, J = 11.2 Hz, 2H), 1.87 (dd, J = 23.7, 8.8 Hz, 3H), 1.69 (ddd, J = 15.8, 14.9, 9.7 Hz, 3H), 1.61- 1.23 (m, 8H), 1.00 (t, J = 7.4 Hz, 3H). MS m/z 467.0 [M + 1]+.
1H NMR (400 MHz, cd3od) δ 7.84 (s, 1H), 6.83 (d, J = 3.5 Hz, 1H), 6.73 (d, J = 3.4 Hz, 1H), 4.49 (s, 2H), 4.19-4.08 (m, 1H), 4.06-3.74 (m, 4H), 3.62-3.53 (m, 1H), 3.52-3.45 (m, 2H), 2.11-1.96 (m, 4H), 1.70-1.61 (m, 2H), 1.59-1.47 (m, 2H), 1.48-1.32 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 430.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 7.84 (s, 1H), 6.83 (d, J = 3.5 Hz, 1H), 6.73 (d, J = 3.4 Hz, 1H), 4.52 (s, 2H), 4.18-4.09 (m, 1H), 3.63-3.39 (m, 7H), 2.45-2.29 (m, 4H), 2.19-1.94 (m, 4H), 1.72-1.60 (m, 2H), 1.60-1.48 (m, 2H), 1.46-1.32 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 464.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 7.84 (s, 1H), 6.79 (d, J = 3.4 Hz, 1H), 6.71 (d, J = 3.4 Hz, 1H), 4.66 (t, J = 11.1 Hz, 4H), 4.57 (s, 2H), 4.18-4.09 (m, 1H), 3.63-3.54 (m, 1H), 3.54- 3.40 (m, 2H), 2.11-1.95 (m, 4H), 1.69-1.62 (m, 2H), 1.60- 1.49 (m, 2H), 1.48-1.33 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 436.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.02 (d, J = 9.5 Hz, 1H), 7.26 (t, J = 3.9 Hz, 1H), 6.86-6.78 (m, 1H), 5.00 (ddd, J = 11.6, 8.0, 3.6 Hz, 1H), 4.30-4.20 (m, 1H), 4.19-4.11 (m, 1H), 3.63-3.55 (m, 2H), 3.54- 3.41 (m, 2H), 3.23-3.10 (m, 2H), 2.94-2.84 (m, 3H), 2.65 (s, 1H), 2.25-2.13 (m, 4H), 2.10-1.99 (m, 2H), 1.98- 1.85 (m, 2H), 1.72-1.61 (m, 4H), 1.57-1.51 (m, 1H), 1.50- 1.34 (m, 3H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 471.30 [M + 1]+.
A solution of 2,4-dichloro-5-iodopyrimidine (456 mg, 2 mmol) and 3-aminocyclobutanol (183 mg, 2.1 mmol) in iPrOH (6.0 mL) was stirred under microwave irradiation at 80° C. for 20 min, then BuNH2 (1.0 mL) was added. The resulting reaction mixture was stirred under microwave irradiation at 100° C. for 30 min, then quenched with brine and extracted with CH2Cl2 (3×). The combined organic layers were dried (Na2SO4) and concentrated. The residue was the dissolved in a mixture of DMF/H2O (8.0 mL/2.0 mL). To this solution was added lithium 2-pyridinyl trihydroxyborate (882 mmol, 6.0 mmol), copper bromide (57.4 mg, 0.40 mmol), Potassium carbonate (828 mg, 6.0 mmol) and PdCl2(dppf) (164 mg, 0.20 mmol). The reaction mixture was heated at 120° C. for 30 min. Then it was diluted with EtOAc (15 mL) after cooled to room temperature. The suspension was filtered through a short pad of celite, which was washed with ethyl acetate. The filtrate was washed with water (2×30 mL), dried (MgSO4) and concentrated. The residue was purified on the ISCO to provide trans-3-((2-(butylamino)-5-(pyridin-2-yl)pyrimidin-4-yl)amino)cyclobutanol (UNC2963A) (326 mg, 52% (over three steps)). 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J=5.1 Hz, 1H), 8.27 (s, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.57-7.37 (m, 1H), 4.77-4.64 (m, 1H), 4.53-4.41 (m, 1H), 3.75-3.55 (m, 1H), 3.49 (s, 2H), 2.43 (t, J=6.2 Hz, 4H), 1.64 (dd, J=14.8, 7.5 Hz, 2H), 1.44 (dd, J=15.0, 7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS m/z 314.0 [M+1]+;
1H NMR
1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 5.1 Hz, 1H), 8.27 (s, 1H), 8.07 (t, J = 7.9 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.58-7.47 (m, 1H), 4.22-4.04 (m, 1H), 3.75-3.53 (m, 1H), 3.48 (s, 2H), 2.84 (d, J = 7.0 Hz, 2H), 2.22 (d, J = 11.0 Hz, 2H), 1.95 (d, J= 12.5 Hz, 2H), 1.68 (ddd, J = 22.3, 10.9, 5.5 Hz, 3H), 1.59- 1.33 (m, 4H), 1.22 (dd, J = 25.7, 12.1 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 355.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.76 (d, J = 5.2 Hz, 1H), 8.26 (t, J = 7.6 Hz, 1H), 8.17 (s, 1H), 8.00 (d, J = 8.1 Hz, 1H), 7.79-7.63 (m, 1H), 3.75-3.58 (m, 4H), 3.61-3.44 (m, 2H), 1.97-1.83 (m, 2H), 1.66 (dt, J = 14.9, 7.3 Hz, 2H), 1.44 (dq, J = 14.5, 7.3 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 326.0 [M + 1]+; LC-MS (ESI+): tR = 4.195 min, MS m/z 302.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 5.1 Hz, 1H), 8.22 (s, 1H), 8.07 (t, J = 7.8 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.61-7.41 (m, 1H), 3.64 (t, J = 6.9 Hz, 2H), 3.55 (t, J = 6.3 Hz, 2H), 3.49-3.41 (m, 2H), 1.72 (dd, J = 14.4, 7.1 Hz, 2H), 1.68-1.62 (m, 2H), 1.58 (dt, J = 13.1, 6.7 Hz, 2H), 1.46 (ddd, J = 22.4, 13.0, 7.6 Hz, 4H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 330.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.67 (dd, J = 4.3, 0.8 Hz, 1H), 8.05 (td, J = 7.8, 1.7 Hz, 1H), 7.95 (s, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.53 (dd, J = 7.6, 5.1 Hz, 1H), 3.71 (s, 4H), 3.50 (s, 2H), 3.24 (s, 4H), 1.65 (dt, J = 14.9, 7.2 Hz, 2H), 1.43 (dd, J = 15.0, 7.5 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). MS m/z 313.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.63 (d, J = 5.0 Hz, 1H), 8.38 (s, 1H), 8.07-7.88 (m, 2H), 7.47-7.40 (m, 1H), 4.47 (s, 1H), 3.72-3.55 (m, 1H), 3.47 (dd, J = 13.4, 4.0 Hz, 3H), 3.21 (d, J = 11.5 Hz, 2H), 2.36 (d, J = 11.1 Hz, 2H), 1.93 (dd, J = 21.0, 10.4 Hz, 2H), 1.66 (dt, J = 15.0, 7.4 Hz, 2H), 1.45 (dd, J = 15.0, 7.4 Hz, 2H), 0.99 (t, J = 7.3 Hz, 3H). MS m/z 327.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.01 (t, J = 7.7 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.55-7.40 (m, 1H), 3.67 (t, J = 16.8 Hz, 3H), 3.50 (s, 1H), 3.42 (d, J = 12.7 Hz, 2H), 2.99 (t, 7= 11.7 Hz, 2H), 2.11 (d, J = 3.7 Hz, 1H), 2.02 (d, J = 13.8 Hz, 2H), 1.71-1.61 (m, 2H), 1.54 (d, J = 13.2 Hz, 2H), 1.45 (dd, J = 15.0, 7.5 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 341.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.62 (d, J = 5.0 Hz, 1H), 8.25 (s, 1H), 8.01-7.91 (m, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.44- 7.34 (m, 1H), 3.67 (dd, J = 8.9, 5.0 Hz, 2H), 3.60 (t, J = 6.4 Hz, 2H), 3.48 (d, J = 8.0 Hz, 2H), 1.84-1.72 (m, 2H), 1.71- 1.56 (m, 4H), 1.43 (dd, J = 15.0, 7.5 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H). MS m/z 316.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.81 (d, J = 5.2 Hz, 1H), 8.36 (t, J = 7.7 Hz, 1H), 8.17 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.88-7.74 (m, 1H), 3.78 (t, J = 5.2 Hz, 2H), 3.72 (d, J = 4.6 Hz, 2H), 3.51 (s, 2H), 1.66 (dt, J = 14.9, 7.4 Hz, 2H), 1.44 (dd, J = 15.0, 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 288.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.68 (d, J = 4.9 Hz, 1H), 8.39 (s, 1H), 8.07-7.92 (m, 2H), 7.58-7.38 (m, 3H), 6.83 (t, J= 6.0 Hz, 2H), 3.38 (d, J = 6.5 Hz, 2H), 1.59 (dd, J = 14.5, 7.3 Hz, 2H), 1.46- 1.32 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H). MS m/z 336.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.72 (d, J = 4.9 Hz, 1H), 8.55 (s, 1H), 7.98 (dd, J = 15.0, 5.8 Hz, 4H), 7.47 (dd, J = 8.8, 4.0 Hz, 3H), 3.53-3.38 (m, 2H), 1.68- 1.59 (m, 2H), 1.41 (d, J = 7.0 Hz, 2H), 1.28-1.13 (m, 2H), 0.95 (t, J = 8.0 Hz, 3H). MS m/z 335.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.59 (d, J = 4.9 Hz, 1H), 8.32 (s, 1H), 7.91 (ddd, J = 20.9, 13.7, 5.0 Hz, 1H), 7.47-7.30 (m, 1H), 4.15 (d, J = 4.3 Hz, 2H), 3.47 (dd, J = 7.0, 3.8 Hz, 2H), 3.20 (s, 2H), 2.27 (s, 2H), 2.16 (s, 2H), 1.66 (dd, J = 14.5, 7.2 Hz, 2H), 1.59 (dd, J = 16.5, 7.4 Hz, 2H), 1.44 (td, J= 14.8, 7.3 Hz, 2H), 0.98 (t, 7.4 Hz, 3H). MS m/z 341.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.67 (d, J = 5.0 Hz, 1H), 8.27 (s, 1H), 8.05 (dd, J = 11.1, 4.5 Hz, 1H), 7.94 (d, J = 8.1 Hz, 1H), 7.52 (dd, J = 7.2, 5.5 Hz, 1H), 3.59-3.46 (m, 4H), 3.07 (ddd, J = 11.9, 8.2, 4.0 Hz, 1H), 2.08 (d, J = 9.4 Hz, 2H), 1.96 (d, J = 12.2 Hz, 2H), 1.77 (d, J = 3.1 Hz, 1H), 1.66 (dt, J= 14.9, 7.4 Hz, 2H), 1.52-1.33 (m, 4H), 1.22 (dd, J = 24.8, 11.1 Hz, 2H), 0.99 (t, J = 7.4 Hz, 3H). MS m/z 355.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.65- 8.52 (m, 1H), 8.28 (s, 1H), 7.91 (dt, J = 18.9, 8.1 Hz, 2H), 7.50-7.34 (m, 1H), 4.20 (d, J = 3.6 Hz, 1H), 3.46 (s, 2H), 2.02 (s, 2H), 1.80 (s, 2H), 1.65 (dt, J= 14.8, 7.3 Hz, 3H), 1.43 (td, J = 14.8, 7.4 Hz, 7H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 326.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 5.2 Hz, 1H), 8.25 (t, J = 7.5 Hz, 1H), 8.18 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.76-7.58 (m, 1H), 4.82-4.73 (m, 1H), 4.37 (dt, J = 8.5, 2.9 Hz, 1H), 3.54 (d, J = 12.6 Hz, 2H), 2.38-2.23 (m, 1H), 2.19-2.11 (m, 1H), 2.10-2.01 (m, 1H), 1.86-1.77 (m, 1H), 1.67 (dt, J = 14.8, 7.2 Hz, 4H), 1.45 (dq, J = 14.5, 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). MS m/z 328.0 [M + 1]+.
A solution of 2,4-dichloro-5-iodopyrimidine (2.6 g, 10 mmol) and 4-aminocyclohexanol (1.27 g, 11 mmol) in iPrOH (60 mL) was stirred at room temperature overnight, then diluted with CH2Cl2 and washed by brine. The organic layer was dried (Na2SO4) and concentrated. The residue was purified on ISCO to afford trans-4-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)cyclohexanol as a white solid (3.19 g, >99%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 5.10 (d, J=7.2 Hz, 1H), 3.97 (dtd, J=11.1, 7.3, 3.8 Hz, 1H), 3.74-3.59 (m, 1H), 2.13 (d, J=12.4 Hz, 2H), 2.02 (d, J=12.4 Hz, 2H), 1.58 (d, J=25.3 Hz, 1H), 1.44 (ddd, J=23.2, 12.9, 3.2 Hz, 2H), 1.30 (ddd, J=24.2, 12.8, 3.1 Hz, 2H). 13C NMR (101 MHz, cdcl3) δ 170.33 (s), 156.85 (s), 155.07 (s), 99.73 (s), 69.70 (s), 49.15 (s), 33.78 (s), 30.41 (s), 14.34 (d, J=3.7 Hz). LC-MS (ESI+): tR=5.104 min, MS m/z 318.0 [M+1]+;
A solution of trans-4-((5-bromo-2-(methylthio)pyrimidin-4-yl)amino)cyclohexanol (2.18 g, 6.36 mmol) in a mixture of DMF/H2O (16.0 mL/4.0 mL) was added 2-pyridinyl trihydroxyborate lithium (2.80 g, 19.1 mmol), copper bromide (183 mg, 1.27 mmol), potassium carbonate (2.63 g, 19.1 mmol) were and PdCl2(dppf) (519 mg, 0.64 mmol) at room temperature. The reaction mixture was heated at 120° C. for 30 min, and then diluted with EtOAc (15 mL) after cooled to room temperature. The resulting suspension was filtered through a short pad of celite, which was washed with ethyl acetate. The filtrate was washed with water (2×30 mL), dried (MgSO4), and concentrated. The residue was purified by the flash chromatography to provide trans-4-((2-(methylthio)-5-(pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexanol as a white solid (1.06 g, 53%). 1H NMR (400 MHz, CD3OD) δ 8.58-8.49 (m, 1H), 8.43 (s, 1H), 7.85 (ddd, J=10.0, 9.6, 5.0 Hz, 2H), 7.34-7.22 (m, 1H), 4.09 (dd, J=9.4, 5.3 Hz, 1H), 3.69-3.58 (m, 1H), 2.52 (s, 3H), 2.19-2.11 (m, 2H), 1.98 (dd, J=10.7, 7.7 Hz, 2H), 1.50-1.32 (m, 3H). 13C NMR (101 MHz, cd3od) δ 170.96 (s), 158.47 (s), 154.56 (s), 152.22 (s), 147.21 (s), 137.25 (s), 121.55 (s), 119.78 (s), 108.55 (s), 68.89 (s), 33.02 (s), 29.75 (s), 12.66 (d, J=3.6 Hz).
A solution of trans-4-((2-(methylthio)-5-(pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexanol (95 mg, 0.5 mmol) in THF (5 mL) was added mCPBA (130 mg, 0.75 mmol). The reaction mixture was stirred at room temperature for 2 h. Then methylamine (2 mmol) was added. The reaction mixture was heated under microwave irradiation at 150° C. for 30 min. The solvent was removed under reduced pressure. The residue was purified on ISCO to afford trans-4-((2-(methylamino)-5-(pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexanol (UNC3122A) as a light brown solid (120 mg, 80%). 1H NMR (400 MHz, CD3OD) δ 8.73 (d, J=4.5 Hz, 1H), 8.27-8.15 (m, 2H), 8.00 (d, J=8.1 Hz, 1H), 7.71-7.58 (m, 1H), 4.18 (s, 1H), 3.68-3.56 (m, 1H), 3.05 (s, 3H), 2.12 (s, 2H), 2.01 (d, J=10.6 Hz, 2H), 1.46 (dd, J=23.8, 12.8 Hz, 4H). LC-MS (ESI+): tR=3.914 min, MS m/z 300.0 [M+1]+;
1H NMR (400 MHz, CD3OD) δ 8.82-8.70 (m, 1H), 8.32- 8.15 (m, 2H), 8.01 (d, J = 8.1 Hz, 1H), 7.76-7.64 (m, 1H), 4.23-4.10 (m, 1H), 3.69-3.55 (m, 1H), 3.53 (s, 2H), 2.12 (d, J = 11.5 Hz, 2H), 2.01 (d, J = 11.3 Hz, 2H), 1.58-1.36 (m, 4H), 1.30 (t, J = 7.2 Hz, 3H). MS m/z 314.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.74 (dd, J = 23.7, 5.1 Hz, 1H), 8.31 (t, J = 7.7 Hz, 1H), 8.18 (s, 1H), 8.05 (t, J = 12.3 Hz, 1H), 7.79-7.67 (m, 1H), 4.20-4.01 (m, 1H), 3.61 (t, J = 6.3 Hz, 2H), 3.53 (s, 2H), 2.08 (t, J = 12.5 Hz, 2H), 2.00 (d, J = 10.3 Hz, 2H), 1.83-1.71 (m, 2H), 1.63 (dt, J = 13.0, 6.3 Hz, 2H), 1.53-1.35 (m, 4H). MS m/z 358.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.70 (d, J = 4.8 Hz, 1H), 8.23 (s, 1H), 8.17 (t, J = 7.6 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.68-7.58 (m, 1H), 4.20- 4.10 (m, 1H), 3.68 (t, J = 6.1 Hz, 2H), 3.64-3.53 (m, 2H), 2.12 (d, J= 10.1 Hz, 2H), 1.99 (d, J = 10.2 Hz, 2H), 1.95- 1.80 (m, 2H), 1.45 (dd, J = 21.7, 11.6 Hz, 4H). MS m/z 330.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.63 (d, J = 5.0 Hz, 1H), 8.37 (s, 1H), 7.97 (ddd, J = 21.5, 11.2, 4.9 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.52-7.38 (m, 3H), 7.27 (t, J = 7.4 Hz, 1H), 4.07 (ddd, J = 14.7, 9.3, 3.8 Hz, 1H), 3.64 (ddd, J = 14.3, 10.0, 4.1 Hz, 1H), 2.14 (dd, J = 12.9, 2.8 Hz, 2H), 2.00 (dd, J = 13.1, 3.3 Hz, 2H), 1.59-1.44 (m, 2H), 1.39 (ddd, J = 23.3, 12.8, 3.1 Hz, 2H). MS m/z 362.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 5.1 Hz, 1H), 8.24 (s, 1H), 8.07 (dd, J = 11.1, 4.7 Hz, 1H), 7.92 (d, J = 8.2 Hz, 1H), 7.54 (dd, J = 7.1, 5.6 Hz, 1H), 7.35-7.16 (m, 5H), 4.12 (d, J = 3.9 Hz, 1H), 3.73 (s, 2H), 3.68-3.56 (m, 1H), 2.96 (t, J = 7.3 Hz, 2H), 2.13 (d, J = 10.0 Hz, 2H), 2.01 (d, J = 10.0 Hz, 2H), 1.59- 1.38 (m, 4H). MS m/z 390.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 4.9 Hz, 1H), 8.25 (s, 1H), 8.05 (d, J = 7.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.58-7.46 (m, 1H), 4.22- 3.98 (m, 1H), 3.68-3.53 (m, 1H), 3.48 (s, 2H), 2.13 (d, J = 11.7 Hz, 2H), 2.00 (d, J = 11.0 Hz, 2H), 1.75-1.62 (m, 2H), 1.43 (ddd, J = 16.6, 14.1, 9.7 Hz, 8H), 0.94 (t, J = 6.9 Hz, 3H). MS m/z 356.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.74 (d, J = 5.3 Hz, 1H), 8.28-8.18 (m, 2H), 8.00 (d, J = 8.1 Hz, 1H), 7.80-7.64 (m, 1H), 4.22-4.05 (m, 1H), 3.77 (t, J = 5.4 Hz, 2H), 3.61 (dq, J = 15.8, 5.4 Hz, 3H), 2.10 (d, J = 9.9 Hz, 2H), 1.99 (d, J = 10.0 Hz, 2H), 1.44 (q, J = 11.8 Hz, 4H). MS m/z 330.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.64 (d, J = 5.0 Hz, 1H), 8.28 (s, 1H), 8.07 (td, J = 8.0, 1.6 Hz, 1H), 7.93 (d, J = 8.2 Hz, 1H), 7.53 (dd, J = 7.4, 5.3 Hz, 1H), 7.41-7.31 (m, 4H), 7.26 (t, J = 6.8 Hz, 1H), 4.65 (s, 2H), 3.99 (s, 1H), 3.57 (s, 1H), 1.93 (d, J = 5.2 Hz, 4H), 1.47-1.31 (m, 4H). MS m/z 376.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.77 (d, J = 5.1 Hz, 1H), 8.30 (td, J = 7.9, 1.5 Hz, 1H), 8.16 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H), 7.75 (dd, J = 7.1, 5.9 Hz, 1H), 4.09 (dd, J = 12.4, 8.8 Hz, 1H), 3.71 (s, 2H), 3.59 (ddd, J = 9.8, 9.2, 4.1 Hz, 1H), 3.24 (s, 3H), 2.17-2.04 (m, 2H), 2.04-1.97 (m, 2H), 1.70 (dt, J = 15.2, 7.6 Hz, 2H), 1.61-1.32 (m, 6H), 1.01 (t, J = 7.4 Hz, 3H). MS m/z 356.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.66 (d, J = 5.1 Hz, 1H), 8.21 (s, 1H), 8.12-8.01 (m, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.53 (dd, J = 7.4, 5.3 Hz, 1H), 4.08 (td, J = 10.2, 4.8 Hz, 1H), 3.79 (s, 4H), 3.66-3.58 (m, 1H), 2.13 (d, J = 11.1 Hz, 2H), 2.05-1.92 (m, 2H), 1.84-1.69 (m, 6H), 1.56-1.36 (m, 4H). MS m/z 354.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.62 (d, J = 5.0 Hz, 1H), 8.28 (s, 1H), 8.09-7.92 (m, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.44 (dd, J = 7.0, 5.5 Hz, 1H), 4.09 (t, J = 10.3 Hz, 1H), 3.89 (s, 1H), 3.65 (tt, J = 8.4, 4.1 Hz, 1H), 2.15 (d, J = 11.2 Hz, 2H), 2.02 (d, J = 11.9 Hz, 4H), 1.94-1.78 (m, 2H), 1.69 (d, J = 12.5 Hz, 1H), 1.62-1.20 (m, 9H). MS m/z 368.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.67 (s, 1H), 8.23 (s, 1H), 8.11 (d, J = 7.4 Hz, 1H), 7.95 (d, J = 7.1 Hz, 1H), 7.56 (s, 1H), 4.24-4.07 (m, 2H), 3.69- 3.58 (m, 1H), 2.12 (d, J = 12.4 Hz, 2H), 2.00 (d, J = 9.9 Hz, 2H), 1.72-1.35 (m, 8H), 1.29 (d, J = 6.6 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H). MS m/z 356.0 [M + 1]+.
1H NMR (400 MHz, CD3OD) δ 8.67 (d, J = 4.9 Hz, 1H), 8.24 (s, 1H), 8.10 (t, J = 7.7 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.61-7.46 (m, 1H), 4.20- 4.07 (m, 1H), 3.71-3.55 (m, 1H), 3.44 (s, 2H), 2.12 (d, J = 11.9 Hz, 2H), 2.07-1.91 (m, 2H), 1.80-1.61 (m, 2H), 1.59- 1.35 (m, 4H), 1.01 (t, J = 7.4 Hz, 3H). MS m/z 328.0 [M + 1]+.
5-Bromo-2,4-dichloropyrimidine (51 g, 223.8 mmol) was dissolved in anhydrous dioxane (150 mL) at 0° C. Then trans-4-aminocyclohexanol (26.3 g, 228.3 mmol) was added in several portions, followed by the addition of DIEA (37.6 g, 290.9 mmol). The resulting mixture was stirred at 0° C. for 5 h and at room temperature for 3 h, quenched with water (100 mL) and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), and concentrated. The residue was recrystallized from a mixture of EtOAc/hexane to provide trans-4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexanol (55 g) as white solid, which was used in the next step without further purification.
A mixture of trans-4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexanol (5.50 g, 17.94 mmol), bis(pinacolato)diboron (6.83 g, 26.90 mmol), Pd(dppf)2Cl2 (732 mg, 0.90 mmol) and KOAc (5.28 g, 53.80 mmol) in anhydrous dioxane (125 mL) was thoroughly degassed and heated under N2 atmosphere at 90° C. for 75 min. The hot mixture was then filtered through a pad of celite and concentrated, the residue was purified on ISCO (to remove most of unreacted trans-4-((5-bromo-2-chloropyrimidin-4-yl)amino)cyclohexanol) followed by a further purification on the reversed ISCO (elute solvents containing 0.1% TFA) to provide 2-chloro-4-((trans-4-hydroxycyclohexyl)amino)pyrimidin-5-yl)boronic acid (1.84 g, 36% over 3 steps). 1H NMR (400 MHz, cd3od) δ 7.98 (s, 1H), 3.99-3.90 (m, 1H), 3.64-3.56 (m, 1H), 2.07-2.00 (m, 2H), 2.00-1.91 (m, 2H), 1.48-1.34 (m, 4H); MS m/z 272.30 [M+H]+.
A mixture of (2-chloro-4-((trans-4-hydroxycyclohexyl)amino) pyrimidin-5-yl)boronic acid (45 mg, 0.166 mmol), 4-((2-bromopyridin-4-yl)methyl)morpholine (85.2 mg, 0.33 mmol), Pd2(dba)3 (7.6 mg, 0.008 mmol), PCy3 (6.9 mg, 0.025 mmol), K3PO4 (0.33 mL, 1M solution in deionized water) and butylamine (50 mg, 0.66 mmol) in a 10 mL microwave tube was degassed and filled with N2 (3×). The resulting mixture was heated at 120° C. under microwave irradiation for 20 min, then quenched with water, and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), and concentrated. The residue was purified on HPLC to provide trans-4-((2-(butylamino)-5-(4-(morpholinomethyl)pyridin-2-yl)pyrimidin-4-yl)amino)cyclohexanol (UNC3015A) (54.5 mg, 75%) as a white solid. 1H NMR (400 MHz, cd3od) δ 8.72-8.66 (m, 1H), 8.42-8.34 (m, 1H), 8.04 (s, 1H), 7.52-7.48 (m, 1H), 4.43 (s, 2H), 4.19-4.09 (m, 1H), 3.93-3.83 (m, 3H), 3.70-3.60 (m, 1H), 3.56-3.42 (m, 2H), 3.37-3.30 (m, 3H), 2.20-2.11 (m, 2H), 2.07-1.95 (m, 2H), 1.70-1.62 (m, 2H), 1.55-1.36 (m, 5H), 0.99 (t, J=7.4 Hz, 3H); MS m/z 441.30 [M+H]+.
1H NMR (400 MHz, cd3od) δ 8.76-8.71 (m, 1H), 8.25-8.19 (m, 1H), 7.76-7.71 (m, 1H), 7.64-7.57 (m, 1H), 4.38 (s, 2H), 4.20-4.07 (m, 1H), 3.91- 3.74 (m, 4H), 3.55-3.45 (m, 2H), 3.24-3.08 (m, 4H), 2.16- 2.03 (m, 1H), 2.02-1.87 (m, 3H), 1.75-1.53 (m, 3H), 1.54- 1.40 (m, 3H), 1.40-1.28 (m, 3H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 441.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.32 (d, J = 1.4 Hz, 1H), 8.02 (s, 1H), 7.92 (d, J = 1.4 Hz, 1H), 4.15-4.06 (m, 1H), 3.66- 3.59 (m, 1H), 3.50-3.36 (m, 2H), 2.17-2.08 (m, 2H), 2.03- 1.94 (m, 2H), 1.69-1.58 (m, 2H), 1.54-1.35 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H); MS m/z 358.25 [M + H]+.
1H NMR (400 MHz, dmso-d6) δ 10.50 (d, J = 6.6 Hz, 1H), 8.66 (s, 1H), 8.41 (d, J = 9.2 Hz, 1H), 8.33-8.27 (m, 1H), 8.25 (d, J = 9.2 Hz, 1H), 4.10- 3.96 (m, 2H), 3.51-3.46 (m, 2H), 3.41-3.35 (m, 2H), 2.07- 1.96 (m, 2H), 1.89-1.81 (m, 2H), 1.61-1.51 (m, 2H), 1.48- 1.39 (m, 2H), 1.37-1.25 (m, 4H), 0.91 (t, J = 7.3 Hz, 3H); MS m/z 387.25 [M + H]+.
1H NMR (400 MHz, cd3od) δ 7.87 (s, 1H), 7.76 (s, 1H), 4.14-4.06 (m, 1H), 4.04 (s, 3H), 3.62-3.55 (m, 1H), 3.52- 3.35 (m, 2H), 2.17-2.08 (m, 2H), 2.04-1.95 (m, 2H), 1.69- 1.57 (m, 2H), 1.50-1.35 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H); MS m/z 388.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.41 (s, 1H), 8.20 (d, J = 10.1 Hz, 1H), 7.71 (d, J = 10.0 Hz, 1H), 4.22-4.11 (m, 1H), 3.78- 3.65 (m, 4H), 3.66-3.57 (m, 1H), 3.55-3.42 (m, 2H), 2.25- 2.08 (m, 6H), 2.07-1.95 (m, 2H), 1.72-1.61 (m, 2H), 1.57- 1.32 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H); MS m/z 412.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.07 (s, 1H), 7.71 (s, 1H), 4.14-4.04 (m, 1H), 3.71-3.63 (m, 1H), 3.45 (s, 2H), 2.75 (s, 3H), 2.19-2.11 (m, 2H), 2.03- 1.95 (m, 2H), 1.70-1.59 (m, 2H), 1.54-1.36 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H); MS m/z 362.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.24 (s, 1H), 7.69 (s, 1H), 4.80 (s, 2H), 4.15-1.07 (m, 1H), 3.69-3.60 (m, 1H), 3.53-3.41 (m, 2H), 2.20-2.11 (m, 2H), 2.05-1.96 (m, 2H), 1.70-1.60 (m, 2H), 1.55-1.36 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H); MS m/z 378.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.31 (s, 1H), 7.85 (d, J = 3.4 Hz, 1H), 7.60 (d, J = 3.4 Hz, 1H), 4.17-1.09 (m, 1H), 3.69- 3.62 (m, 1H), 3.55-3.41 (m, 2H), 2.21-2.12 (m, 2H), 2.05- 1.97 (m, 2H), 1.70-1.61 (m, 2H), 1.56-1.37 (m, 6H), 0.98 (t, J = 7.4 Hz, 3H); MS m/z 348.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.45-8.39 (m, 1H), 8.14-8.10 (m, 1H), 7.75-7.70 (m, 1H), 5.17-5.02 (m, 1H), 4.39-1.23 (m, 1H), 4.22-4.13 (m, 1H), 3.72-3.61 (m, 1H), 3.57-3.42 (m, 2H), 2.75-2.67 (m, 3H), 2.27-2.12 (m, 3H), 2.08-1.93 (m, 2H), 1.74-1.64 (m, 3H), 1.58-1.51 (m, 1H), 1.48-1.41 (m, 3H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 357.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.32 (s, 1H), 8.07 (d, J = 9.5 Hz, 1H), 7.28 (d, J = 9.5 Hz, 1H), 4.21-4.14 (m, 1H), 4.12 (s, 3H), 3.70-3.61 (m, 1H), 3.57-3.39 (m, 2H), 2.16 (d, J = 10.9 Hz, 2H), 2.02 (d, J = 9.8 Hz, 2H), 1.73-1.62 (m, 2H), 1.60-1.49 (m, 2H), 1.49-1.35 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 373.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.20 (s, 1H), 7.82 (d, J = 9.6 Hz, 1H), 7.09 (d, J = 9.6 Hz, 1H), 4.19-4.08 (m, 1H), 3.69- 3.60 (m, 1H), 3.52-3.37 (m, 2H), 2.73-2.64 (m, 1H), 2.16 (d, J = 10.8 Hz, 2H), 2.03 (d, J = 11.3 Hz, 2H), 1.72-1.59 (m, 2H), 1.56-1.40 (m, 5H), 0.99 (t, J = 7.4 Hz, 3H), 0.91-0.81 (m, 2H), 0.61-0.51 (m, 2H); MS m/z 398.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.23 (s, 1H), 7.92 (d, J = 9.9 Hz, 1H), 7.44 (d, J = 9.9 Hz, 1H), 4.21-4.13 (m, 1H), 3.77- 3.67 (m, 4H), 3.69-3.63 (m, 1H), 3.64-3.53 (m, 4H), 3.55- 3.42 (m, 2H), 2.16 (d, J = 10.5 Hz, 2H), 2.03 (d, J = 9.7 Hz, 2H), 1.72-1.62 (m, 2H), 1.61- 1.51 (m, 2H), 1.49 (s, 9H), 1.47-1.38 (m, 3H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 527.40 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.49 (d, J = 1.1 Hz, 1H), 8.18 (s, 1H), 6.85 (d, J = 0.7 Hz, 1H), 4.15-4.07 (m, 1H), 3.67- 3.59 (m, 1H), 3.55-3.41 (m, 2H), 2.17-2.08 (m, 2H), 2.05- 1.96 (m, 2H), 1.70-1.61 (m, 2H), 1.55-1.35 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 358.25 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.90 (d, J = 1.6 Hz, 1H), 8.50 (d, J = 1.5 Hz, 1H), 8.33 (s, 1H), 4.18-4.10 (m, 1H), 3.68- 3.60 (m, 1H), 3.49 (s, 2H), 2.62 (s, 3H), 2.20-2.09 (m, 2H), 2.06-1.95 (m, 2H), 1.71- 1.63 (m, 2H), 1.54-1.37 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 389.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.55 (s, 1H), 8.12 (s, 1H), 6.80 (s, 1H), 4.16-4.04 (m, 1H), 3.69-3.57 (m, 1H), 3.56-3.38 (m, 2H), 3.00 (s, 3H), 2.21- 2.07 (m, 2H), 2.07-1.91 (m, 2H), 1.76-1.57 (m, 3H), 1.55- 1.33 (m, 5H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 372.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.52 (s, 1H), 8.12 (s, 1H), 6.77 (s, 1H), 4.15-4.06 (m, 1H), 3.66-3.58 (m, 1H), 3.53-3.40 (m, 3H), 2.20-2.07 (m, 2H), 2.05-1.94 (m, 2H), 1.75-1.57 (m, 3H), 1.58-1.30 (m, 6H), 1.26 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 386.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.79 (d, J = 1.1 Hz, 1H), 8.44 (s, 1H), 7.28 (s, 1H), 4.17- 4.08 (m, 1H), 4.03 (s, 3H), 3.71-3.62 (m, 1H), 3.54-3.44 (m, 2H), 2.21-2.12 (m, 2H), 2.06-1.99 (m, 2H), 1.71-1.62 (m, 2H), 1.60-1.50 (m, 2H), 1.50-1.39 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 373.25 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.29 (s, 1H), 8.13 (s, 1H), 7.89 (s, 1H), 4.16-4.09 (m, 1H), 3.65-3.58 (m, 1H), 3.57-3.51 (m, 4H), 3.52-3.42 (m, 2H), 2.23-2.15 (m, 2H), 2.15-2.08 (m, 4H), 2.07-2.01 (m, 2H), 1.71-1.63 (m, 2H), 1.44 (tt, J = 10.6, 5.4 Hz, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 412.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.33 (d, J = 21.0 Hz, 1H), 7.83 (d, J = 11.4 Hz, 1H), 7.59 (d, J = 1.4 Hz, 1H), 4.25-4.04 (m, 2H), 3.87 (s, 3H), 3.64-3.53 (m, 1H), 3.53-3.40 (m, 2H), 2.21-2.11 (m, 2H), 2.11-2.03 (m, 2H), 2.03-1.94 (m, 2H), 1.72-1.58 (m, 3H), 1.53-1.32 (m, 5H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 345.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 7.83 (s, 1H), 7.62-7.58 (m, 1H), 7.45-7.36 (m, 7H), 7.29- 7.21 (m, 4H), 7.21-7.14 (m, 4H), 4.13-4.05 (m, 1H), 3.68- 3.58 (m, 1H), 3.51-3.36 (m, 2H), 2.94-2.81 (m, 1H), 2.19- 2.05 (m, 2H), 2.04-1.94 (m, 211), 1.94-1.82 (m, 2H), 1.82- 1.72 (m, 1H), 1.70-1.59 (m, 2H), 1.56-1.35 (m, 6H), 1.04- 0.94 (m, 3H); MS m/z 573.35 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.57 (s, 1H), 8.27-8.21 (m, 1H), 7.20 (d, J = 6.4 Hz, 1H), 4.20-4.12 (m, 1H), 3.69-3.61 (m, 1H), 3.57-3.44 (m, 2H), 2.12 (d, J = 11.9 Hz, 2H), 2.05 (d, J = 11.0 Hz, 2H), 1.73- 1.58 (m, 4H), 1.50-1.34 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 358.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 7.99 (d, J = 2.9 Hz, 1H), 7.92 (d, J = 2.9 Hz, 1H), 7.83 (s, 1H), 4.18-4.09 (m, 1H), 3.59- 3.44 (m, 3H), 2.06-1.93 (m, 4H), 1.73-1.63 (m, 2H), 1.54- 1.20 (m, 7H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 358.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.33 (s, 1H), 7.87 (d, J = 3.4 Hz, 1H), 7.62 (d, J = 3.4 Hz, 1H), 4.20-4.10 (m, 1H), 3.72- 3.63 (m, 1H), 3.64-3.51 (m, 2H), 2.24-2.13 (m, 2H), 2.08- 1.97 (m, 2H), 1.61-1.54 (m, 3H), 1.52-1.42 (m, 3H), 0.81- 0.72 (m, 1H), 0.55-0.46 (m, 2H), 0.17-0.08 (m, 2H); MS m/z 360.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.48 (s, 1H), 7.56 (s, 1H), 4.15-4.06 (m, 1H), 3.74-3.64 (m, 1H), 3.58-3.39 (m, 2H), 2.65 (s, 3H), 2.60 (s, 3H), 2.20 (d, J = 10.8 Hz, 2H), 2.03 (d, J = 11.0 Hz, 2H), 1.71-1.61 (m, 2H), 1.60-1.38 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 403.25 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.26 (s, 1H), 7.73 (s, 1H), 4.19-4.09 (m, 1H), 3.92 (s, 2H), 3.72-3.62 (m, 1H), 3.59- 3.36 (m, 4H), 2.89 (s, 3H), 2.77-2.32 (m, 3H), 2.16 (d, J = 10.8 Hz, 2H), 2.02 (d, J = 11.3 Hz, 2H), 1.80-1.58 (m, 3H), 1.63-1.25 (m, 7H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 460.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.39 (s, 1H), 8.31 (s, 1H), 4.19-4.10 (m, 1H), 3.70-3.63 (m, 1H), 3.55-3.45 (m, 2H), 2.17 (d, J = 11.2 Hz, 2H), 2.03 (d, J = 11.0 Hz, 2H), 1.71- 1.62 (m, 2H), 1.60-1.36 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 391.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.30 (s, 1H), 7.42 (s, 1H), 4.71 (d, J = 0.9 Hz, 2H), 4.18-4.10 (m, 1H), 3.74-3.64 (m, 1H), 3.58-3.39 (m, 2H), 2.22-2.12 (m, 2H), 2.07-1.98 (m, 2H), 1.72-1.63 (m, 2H), 1.62-1.51 (m, 2H), 1.51-1.38 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 378.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.36 (s, 1H), 8.26 (s, 1H), 4.15-4.07 (m, 1H), 3.71-3.62 (m, 1H), 3.55-3.45 (m, 2H), 2.17 (d, J = 11.6 Hz, 2H), 2.04 (d, J = 10.4 Hz, 2H), 1.71- 1.59 (m, 4H), 1.50-1.38 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 391.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.16 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 4.20-4.10 (m, 1H), 3.75-3.67 (m, 1H), 3.65-3.55 (m, 1H), 3.54-3.41 (m, 2H), 2.23-2.15 (m, 2H), 2.07-1.98 (m, 4H), 1.90-1.82 (m, 2H), 1.75-1.62 (m, 3H), 1.55-1.28 (m, 11H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 440.40 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.27-8.21 (m, 2H), 8.21 (s, 1H), 4.15-4.07 (m, 1H), 3.88- 3.81 (m, 4H), 3.65-3.57 (m, 5H), 3.56-3.42 (m, 2H), 2.21- 2.12 (m, 2H), 2.07-1.99 (m, 2H), 1.71-1.63 (m, 2H), 1.50- 1.37 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 428.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.39 (s, 1H), 8.37 (s, 1H), 4.28-4.10 (m, 1H), 3.77-3.63 (m, 1H), 3.59-3.40 (m, 2H), 2.26-2.12 (m, 2H), 2.11-1.99 (m, 2H), 1.73-1.62 (m, 2H), 1.63-1.52 (m, 2H), 1.52-1.39 (m, 4H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 392.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.18 (s, 1H), 7.52 (d, J = 1.2 Hz, 1H), 4.17-4.08 (m, 1H), 3.70-3.61 (m, 1H), 3.58-3.37 (m, 2H), 2.51 (d, J = 1.1 Hz, 3H), 2.24-2.09 (m, 2H), 2.07- 1.93 (m, 2H), 1.72-1.58 (m, 2H), 1.53-1.40 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 362.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.75 (s, 1H), 8.47 (s, 1H), 8.32 (d, J = 8.0 Hz, 1H), 8.23 (s, 2H), 8.20 (d, J = 7.8 Hz, 1H), 7.70-7.63 (m, 1H), 4.24-4.13 (m, 1H), 3.74-3.63 (m, 1H), 3.51 (t, J = 7.0 Hz, 2H), 2.21 (d, J = 9.8 Hz, 2H), 2.06 (d, J = 9.9 Hz, 2H), 1.74-1.63 (m, 2H), 1.64-1.54 (m, 2H), 1.53- 1.39 (m, 4H), 0.99 (t, J = 7.4 Hz, 3H); MS m/z 463.30 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.33 (s, 1H), 7.88 (d, J = 3.4 Hz, 1H), 7.62 (d, J = 3.4 Hz, 1H), 4.20-4.12 (m, 1H), 3.71- 3.64 (m, 1H), 3.62 (t, J = 6.3 Hz, 2H), 3.58-3.47 (m, 2H), 2.22-2.13 (m, 2H), 2.06-1.97 (m, 2H), 1.90-1.70 (m, 3H), 1.68-1.60 (m, 2H), 1.57-1.41 (m, 4H); MS m/z 364.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.45 (s, 1H), 8.26 (d, J = 0.9 Hz, 1H), 4.23-4.11 (m, 1H), 3.75-3.65 (m, 1H), 3.51 (t, J = 6.7 Hz, 2H), 2.26-2.15 (m, 2H), 2.07-1.95 (m, 2H), 1.73- 1.62 (m, 2H), 1.56-1.39 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 416.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.46 (s, 1H), 8.32-8.26 (m, 1H), 4.20-4.10 (m, 1H), 3.71- 3.62 (m, 1H), 3.51 (t, J = 6.7 Hz, 2H), 2.17 (d, J = 11.1 Hz, 2H), 2.02 (d, J = 10.9 Hz, 2H), 1.72-1.62 (m, 2H), 1.58- 1.39 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 416.20 [M + H]+.
1H NMR (400 MHz, cd3od) δ 8.46 (d, J = 0.9 Hz, 1H), 8.21 (s, 1H), 8.11-8.05 (m, 2H), 7.24-7.18 (m, 2H), 6.82 (s, 1H), 5.08-5.01 (m, 1H), 4.29-4.22 (m, 1H), 3.55-3.44 (m, 2H), 2.28-2.10 (m, 4H), 1.80-1.59 (m, 6H), 1.49- 1.42 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H); MS m/z 480.30 [M + H]+.
The foregoing is illustrative of the present invention, and is not to be construed as limiting thereof. The invention is defined by the following claims, with equivalents of the claims to be included therein.
This application is a 35 U.S.C. §371 national phase entry of PCT Application PCT/US2013/042033, filed May 21, 2013, and published in English on Nov. 28, 2013, as International Publication No. WO 2013/177168, and which claims the benefit of U.S. Provisional Application No. 61/650,000, filed May 22, 2012.
This invention was made with Government support under Grant No. HHSN261200800001E awarded by the National Institutes of Health. The Government has certain rights in the invention.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2013/042033 | 5/21/2013 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2013/177168 | 11/28/2013 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 5958930 | Gangjee et al. | Sep 1999 | A |
| 7589086 | Bondavelli et al. | Sep 2009 | B2 |
| 7897607 | Gyorkos et al. | Mar 2011 | B2 |
| 7956060 | Arai et al. | Jun 2011 | B2 |
| 7998978 | Huang et al. | Aug 2011 | B2 |
| 8324225 | Brain et al. | Dec 2012 | B2 |
| 8362023 | Liu et al. | Jan 2013 | B2 |
| 8415361 | Lemke et al. | Apr 2013 | B2 |
| 8513242 | Chiang et al. | Aug 2013 | B2 |
| 20060025383 | Wishart et al. | Feb 2006 | A1 |
| 20070078140 | Borzilleri et al. | Apr 2007 | A1 |
| 20070105874 | Zhang et al. | May 2007 | A1 |
| 20070225306 | Choi et al. | Sep 2007 | A1 |
| 20070275984 | Imogai et al. | Nov 2007 | A1 |
| 20080248046 | Ni et al. | Oct 2008 | A1 |
| 20080267887 | Yuan et al. | Oct 2008 | A1 |
| 20090012060 | Arai | Jan 2009 | A1 |
| 20100137313 | Boriack-Sjodin | Jun 2010 | A1 |
| 20100247554 | Lemke et al. | Sep 2010 | A1 |
| 20100266604 | Rothlin et al. | Oct 2010 | A1 |
| 20110281867 | Kalman et al. | Nov 2011 | A1 |
| 20110319267 | Ekwuribe et al. | Dec 2011 | A1 |
| 20120035194 | Huang et al. | Feb 2012 | A1 |
| 20120207763 | Brain et al. | Aug 2012 | A1 |
| 20120207764 | Terrett et al. | Aug 2012 | A1 |
| 20120219559 | Chen et al. | Aug 2012 | A1 |
| 20120230991 | Graham et al. | Sep 2012 | A1 |
| 20130029993 | Stadtmueller | Jan 2013 | A1 |
| 20130034862 | Fantl et al. | Feb 2013 | A1 |
| 20130059836 | Wang et al. | Mar 2013 | A1 |
| 20130072382 | Trullinger et al. | Mar 2013 | A1 |
| 20130102587 | Evans et al. | Apr 2013 | A1 |
| 20130137708 | Garske et al. | May 2013 | A1 |
| 20130150368 | Ashcraft et al. | Jun 2013 | A1 |
| 20130266563 | Gokaraju et al. | Oct 2013 | A1 |
| Number | Date | Country |
|---|---|---|
| 2492319 | Apr 2004 | CA |
| 1710246 | Oct 2006 | EP |
| 1803723 | Jul 2007 | EP |
| 2133095 | Dec 2009 | EP |
| 2840080 | Feb 2015 | EP |
| WO 9749706 | Dec 1997 | WO |
| WO 03029209 | Apr 2003 | WO |
| WO 2005009443 | Feb 2005 | WO |
| WO 2005028434 | Mar 2005 | WO |
| WO 2005095382 | Oct 2005 | WO |
| WO 2006035067 | Apr 2006 | WO |
| WO 2007032445 | Mar 2007 | WO |
| WO 2007035963 | Mar 2007 | WO |
| WO 2007041379 | Apr 2007 | WO |
| WO 2007044426 | Apr 2007 | WO |
| WO 2007075554 | Jul 2007 | WO |
| WO 2007113254 | Oct 2007 | WO |
| WO 2007134828 | Nov 2007 | WO |
| WO 2009032694 | Mar 2009 | WO |
| WO 2009047359 | Apr 2009 | WO |
| WO 2010043865 | Apr 2010 | WO |
| WO 2010085597 | Jul 2010 | WO |
| WO 2011103441 | Aug 2010 | WO |
| WO 2010117425 | Oct 2010 | WO |
| WO 2010129802 | Nov 2010 | WO |
| WO 2011029915 | Mar 2011 | WO |
| WO 2011065800 | Jun 2011 | WO |
| WO 2011090760 | Jul 2011 | WO |
| WO 2011146313 | Nov 2011 | WO |
| WO 2012053606 | Apr 2012 | WO |
| WO 2012158795 | Nov 2012 | WO |
| WO 2013032591 | Mar 2013 | WO |
| WO 2013042006 | Mar 2013 | WO |
| WO 2013052417 | Apr 2013 | WO |
| WO 2013124324 | Aug 2013 | WO |
| WO 2013157022 | Oct 2013 | WO |
| WO 2013177168 | Nov 2013 | WO |
| WO 2014062774 | Apr 2014 | WO |
| WO 2014085225 | Jun 2014 | WO |
| PCTUS2015024258 | Apr 2015 | WO |
| PCTUS2015024301 | Apr 2015 | WO |
| PCTUS2015024328 | Apr 2015 | WO |
| PCTUS2015024380 | Apr 2015 | WO |
| PCTUS2015024381 | Apr 2015 | WO |
| PCTUS2015024393 | Apr 2015 | WO |
| PCTUS2015024395 | Apr 2015 | WO |
| PCTUS2015024396 | Apr 2015 | WO |
| Entry |
|---|
| Registry No. 142210-34-2, STN file Registry, Jul. 3, 1992. |
| Examination Report corresponding to European Application No. 13793925.2 dated Nov. 30, 2015. |
| U.S. Appl. No. 14/348,805, The University of North Carolina at Chapel Hill, filed Oct. 17, 2012. |
| U.S. Appl. No. 14/436,356, The University of North Carolina at Chapel Hill, filed Apr. 16, 2015. |
| U.S. Appl. No. 14/678,905, The University of North Carolina at Chapel Hill, filed Apr. 3, 2015. |
| U.S. Appl. No. 14/678,830, The University of North Carolina at Chapel Hill, filed Apr. 3, 2015. |
| U.S. Appl. No. 14/678,678, The University of North Carolina at Chapel Hill, filed Apr. 3, 2015. |
| U.S. Appl. No. 14/678,879, The University of North Carolina at Chapel Hill, filed Apr. 3, 2015. |
| U.S. Appl. No. 14/678,898, The University of North Carolina at Chapel Hill, filed Apr. 3, 2015. |
| U.S. Appl. No. 14/678,540, The University of North Carolina at Chapel Hill, filed Apr. 3, 2015. |
| Aly et al. “Heteroannelations with o-amino aldehyde and o-amino cyano of some pyrazole derivatives” Afinidad, Barcelona, ES (2004) 61, 510-515. |
| Angelillo-Scherrer, A, et al., “Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy”, J. Clin. Invest. (2005) 115 (2), 237-246. |
| Bernsmeier, et al., “Patients with Acute-on-Chronic Liver Failure Have Increased Numbers of Regulatory Immune Cells Expressing the Receptor Tyrosine Kinase MERTK”, Gastroenterology (2015), 1-13. |
| Bhattacharayya, et al., “Enveloped viruses disable innate immune responses in dendritic cells by direct activation of TAM receptors”, Cell Host & Microbe (2013) 14, 136-147. |
| Brindley, et al., “Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein”, Virology (2011) 415, 83-84. |
| Cavasotto et al. “In silico identification of novel EGFR inhibitors with antiproliferative activity against cancer cells” Bioorg. Med. Chem. Lett. (2006) 16, 1969-1974. |
| Chen, et al., “Identification of Gas6 as a ligand for Mer, a neural cell adhesion molecule related receptor tyrosine kinase implicated in cellular transformation”, Oncogene (1997) 14, 2033-2039. |
| Chen, et al, “Mer Receptor tyrosine Kinase Signaling Participates in Platelet Function”, Attetioscler. Thromv Vasc. Biol. (2004) 24, 1118-1123. |
| Christoph, S. et al., “UNC569, a novel small-molecule Mer inhibitor with efficacy against acute lymphoblastic leukemia in vitro and in vivo”, Mol Cancer Ther. (2013) 12(11):2367-77. |
| Cook, et al. “MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis” J. Clin. Invest. (2013) 123, 3231-3242. |
| Earp, S. “Chemical Biology Consortium: Mer Kinase Inhibitor Studies” Presentation at the Chemical Biology Consortium, Jan. 26, 2012. |
| Frye, S. “Academic Drug Discovery: US Perspective and Examples” Presentation at the NCI Translational Science Meeting, Washington DC, Jul. 29, 2011. |
| Frye, S. “Academic Drug Discovery and Chemical Biology”, Presentation at the Northwestern 18th Annual Drug Discovery Symposium. Nov. 13, 2013. |
| Graham, et al., “Cloning and mRNA expression analysis of a novel human protooncogene, c-mer”, Cell Growth Differ. (1994) 5, 647-657. |
| Lee-Sherick, et al. “Efficacy of a Mer and Flt3 tyrosine kinase small molecule inhibitor, UNC1666, in acute myeloid leukemia”, Oncotarget, Advance Publications, Feb. 10, 2015. |
| Linger et al. “Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia” Blood (2013) 122(9), 1599-1609. |
| Liu, J. et al. “Discovery of Novel Small Molecule Mer Kinase Inhibitors for the Treatment of Pediatric Acute Lymphoblastic Leukemia” ACS Med. Chem. Lett. (2012) 3(2), 129-134. |
| Liu, J, et al. “UNC1062, a new and potent Mer inhibitor”, Eur. J. Med. Chem. (2013) 65, 83-93. |
| Meertens, L. et al. “The TIM and TAM families of phosphatidylserine receptors mediate dengue virus entry”, Cell Host & Microbe (2012) 12, 544-557. |
| Mercer, J. & Helenius, A. “Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells”, Science (2008) 320, 531-535. |
| Morizono, et al, “The Soluble Serum Protein Gas6 Bridges Virion Envelope Phosphatidylserine to the TAM Receptor Tyrosine Kinase Axl to mediate Viral Entry”, Cell Host & Microbe ( 2011) 9, 286-298. |
| Morizono and Chen, “Role of Phosphatidyl Receptors in Enveloped Virus Infection”, J. Virology (2014) 88(8), 4275-4290. |
| Paolino, M., et al., “The E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells”, Nature (2014) 507, 508-512. |
| Powell et al., “Highly selective 2,4-diaminopyridine-5-carboxamide inhibitors of Sky kinase”, Bioorg. Med. Chem. Lett. (2013) 23, 1046-1050. |
| Powell et al., “Optimization of highly selective 2,4-diaminopyridine-5-carboxamide inhibitors of Sky kinase”, Bioorg. Med. Chem. Lett. (2013) 23, 1051-1055. |
| Sather, et al., “A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation”, Blood (2007) 109(3), 1026-1033. |
| Schlegel et al., “MER receptor tyrosine kinase is a therapeutic target in melanoma” J. Clin. Invest. (2013) 123(5); 2257-67. |
| Shimojima, et al., “Tyro3 Family-mediated Cell Entry of Ebola and Marburg Viruses”, Journal of Virology (2006) 80(20), 10109-10116. |
| Zhang, W., et al., “Discovery of Mer specific tyrosine kinase inhibitors for the treatment and prevention of thrombosis”, J. Med. Chem. (2013) 56, 9693-9700. |
| Zhang, W., et al., “Pseudo-cyclization through intramolecular hydrogen bond enables discovery of pyridine substituted pyrimidines as new Mer kinase inhibitors”, J. Med. Chem. (2013) 56, 9683-9692. |
| Extended European Search Report, EP 11783985.2, mailed Oct. 15, 2013. |
| Extended European Search Report, EP 12839069.7, mailed May 4, 2015. |
| International Search Report and Written Opinion, PCT/US2011/036215, mailed Aug. 16, 2011. |
| International Search Report and Written Opinion, PCT/US2012/058298, mailed Dec. 7, 2012. |
| International Preliminary Report on Patentability, PCT/US2013/042033, mailed Dec. 4, 2014. |
| International Search Report and Written Opinion, PCT/US2015/24258, mailed Jun. 24, 2015. |
| International Search Report and Written Opinion, PCT/US2015/24301, mailed Jun. 25, 2015. |
| International Search Report and Written Opinion, PCT/US2015/24328, mailed Jun. 25, 2015. |
| International Search Report and Written Opinion, PCT/US2015/24362, mailed Jun. 26, 2015. |
| International Search Report and Written Opinion, PCT/US2015/24373, mailed Jul. 7, 2015. |
| International Search Report and Written Opinion, PCT/US2015/24380, mailed Jul. 1, 2015. |
| International Search Report and Written Opinion, PCT/US2015/24381, mailed Jul. 1, 2015. |
| International Search Report and Written Opinion, PCT/US2013/042033, mailed Aug. 27, 2013. |
| Search Report corresponding to European Application No, 13847985.2 dated May 24, 2016. |
| Search Report corresponding to European Application No. 13858929.6 dated May 3, 2016. |
| Database CAPLUS in STN, Ace. No. 2007:1144983, Guillemont et al., WO 2007/113254 A 1 (Oct. 11, 2007) (abstract). |
| Banker et al. Modern Pharmaceuticals p. 596 (1996). |
| Wolff et al. “Burger's Medicinal Chemistry and Drug Discovery”, John Wiley & Sons, Inc. 5th Ed. vol. 1:975-977 (1995). |
| Database CAPLUS [Online]—Chemical. Abstracts Service, Columbus, Ohio, US; 2004, Ismail, M.A.: “Efficient synthesis of 5-(5-aryl-2-furyl)pyrimidine derivatives”, Database accession No. 2004:551368: & Ismail, M.A,: “Efficient synthesis of 5-(5-aryl-2-furyl)pyrimidine derivatives”, Mansoura Science Bulletin, A: Chemistry, vol. 30, No. 2, 2003, pp. 157-172 (Abstract Only). |
| Ishida et al, “Novel and orally active 5-(1,3,4-oxadiazol-2-yl)pyrimidine derivatives as selective FLT3 inhibitors”, Biorganic & Medicinal Chemistry Letters 18:5472-5477 (2008). |
| Kiyoi et al. “A Novel FLT3 Inhibitor FI-700 Selectively Suppresses the Growth of Leukemia Cells with FLT3 Mutations”, Clin Cancer Res 13(15):4575-4582 (2007). |
| Pawar et al. “Synthesis of 2,4,5-Trisubstituted Pyrimidines”, Indian Journal of Heterocyclic Chemistry 20(12):133-136 (2010). |
| Examination Report corresponding to European Application No. 13793925.2 issued Jul. 22, 2016. |
| Aso et al. “Discovery of pyrrolo[12,3-d]pyrimidin-4-ones as corticotropin-releasing factor 1 receptor antagonists with a carbonyl-based hydrogen bonding acceptor”, Bioorganic & Medicinal Chemistry Letters 21(8):2365-2371 (2011) (Abstract Only). |
| Verma et al. “Targeting Axl and Mer Kinases in Cancer”, Mol Cancer Ther 10(10):1763-73 (2011). |
| Cancer Drug Design and Discovery Neidle, Stephen, ed. (Elsevier/Academic Press, 2008) pp. 427-431. |
| Notification Concerning Transmittal of Copy of International Preliminary Report on Patentability corresponding to International Application No. PCT/US2015/024381 mailed Oct. 20, 2016. |
| Notification Concerning Transmittal of Copy of international Preliminary Report on Patentability corresponding to International Application No. PCT/US2015/024362 mailed Oct. 20, 2016. |
| Notification Concerning Transmittal of Copy of International Preliminary Report on Patentability corresponding to International Application No. PCT/US2015/024328 mailed Oct. 20, 2016. |
| Notification Concerning Transmittal of Copy of International Preliminary Report on Patentability Report on Patentability corresponding to International Application No. PCT/US2015/024258 mailed Oct. 13, 2016. |
| Notification Concerning Transmittal of Copy of International Preliminary Report on Patentability corresponding to International Application No. PCT/US2015/024373 mailed Oct. 20, 2016. |
| Notification Concerning Transmittal of Copy of International Preliminary Report on Patentability corresponding to International Application No. PCT/US2015/024380 mailed Oct. 20, 2016. |
| Notification Concerning Transmittal of Copy of International Preliminary Report on Patentability corresponding to International Application No. PCT/US2015/024301 mailed Oct. 20, 2016. |
| Yu et al. “3D-QSAR modeling and molecular docking study on Mer kinase inhibitors of pyridine-substituted pyrimidines”, Mol Divers 19:135-147 (2015). |
| Zhang et al. “Pseudo-Cyclization through Intramolecular Hydrogen Bond Enables Discovery of Pyridine Substituted Pyrimidines as New Mer Kinase”, J. Med. Chem. 56:9683-9692 (2013). |
| Number | Date | Country | |
|---|---|---|---|
| 20150038481 A1 | Feb 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61650000 | May 2012 | US |
