New therapy for pain

Abstract

The present application describes novel SOS1 inhibitors for the treatment of pain and cancer.

Description

[0001] This invention describes compounds that bind to the Son of Sevenless homolog 1 receptor (SOS1) protein, thereby inhibiting the cascade pathway and leading to pain relief.

[0002] New treatments for pain management are still needed. Many of the most effective and frequently prescribed pain management methods are opioids. These substances have a high risk of abuse and addiction. However, to date, no treatment with comparable efficacy has been found to replace them as first-line treatments. To provide a paradigm shift in pain management, new targets and pathways in the body need to be identified.

[0003] This application describes a novel SOS1 inhibitor suitable for the treatment of pain and cancer.

[0004] Recently, SOS1 inhibitors have been identified as mediating several conditions:

[0005] WO2019 / 122129 describes benzylamino-substituted pyridopyrimidines as SOS1 inhibitors for the treatment of cancerous growths in oncology.

[0006] WO2018 / 115380 describes benzylamino-substituted quinazolines as SOS1 inhibitors, which can similarly be used to treat cancerous growths in oncology.

[0007] WO2018 / 172250 describes a class of 2-methylquinazoline compounds for the treatment of hyperproliferative diseases.

[0008] WO2019 / 201848 describes another class of 2-methylquinazoline compounds for the treatment of hyperproliferative diseases.

[0009] Other SOS1 inhibitors are taught in the Proceedings of the National Academy of Sciences of the United States of America (2019), 116(7), 2551-2560.

[0010] This invention provides novel SOS1 inhibitors, novel SOS1 inhibitors for treating pain, and novel SOS1 inhibitors for treating cancer.

[0011] Attached Figure

[0012] Figure 1The NGF signaling pathway leading to pain and clinical drugs to validate this pathway. NGF binds to TrkA, and subsequent signal transduction ultimately leads to the nuclear accumulation of diphosphorylated extracellular signal-regulated kinases (dppERKnuc) in neurons, upregulating pain genes.

[0013] Figure 2 Clinical genetic validation of the target. In NF1, the patient has a mutation in the interneuronal interstitial protein (NF1). This mutation leads to loss of function and blocks RAS. GTP The GTP is normally converted into GDP, thereby increasing RAS. GTP The concentration of these substances leads to excessive signal transduction, tumors, and pain. Invention Overview

[0015] This application describes novel SOS1 inhibitors, their use in treating pain, and their use in treating cancer.

[0016] This invention provides compounds of formula (I).

[0017]

[0018] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0019] X is N or CR 25

[0020] R 1 Selected from 4-7 membered saturated heterocycles containing N, optionally containing additional O, N, or S atoms, or an S(O)2 group, wherein the heterocycle optionally contains:

[0021] (i) ether bridge, or

[0022] (ii) Connecting another 4-7 member N-containing saturated heterocycle to form a spirobicyclic group; or

[0023] (iii) Connected to another 3-6 N-containing saturated heterocycle, such that each ring shares two atoms, wherein the saturated heterocycle is optionally incorporated into the C(O) portion;

[0024] The monocyclic or bicyclic heterocycle is optionally substituted by 1-3 substituents, each of which is independently selected from NC(O)C. 1-6 Alkyl, H, N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, OH and OC 1-6 Alkyl, HC(O)C 1-6Alkyl, halogen, and Ph

[0025] R 2 Selected from

[0026] and

[0027] R 3 Is it H or NH2?

[0028] R 4 It is CF3, CF2CH2OH, CN

[0029] R 5 It is halogen

[0030] R 6 It is H

[0031] R 7 It is H

[0032] R 8 It is Ph, which is substituted at the ortho position by CH2NHCH3.

[0033] R 25 It consists of H, OCH3, F, and CN.

[0034] This invention provides an SOS1 inhibitor for the treatment of pain.

[0035] This invention provides an SOS1 inhibitor for the treatment of cancer.

[0036] This invention provides novel compounds as described in the appended claims, their use as pharmaceuticals, pharmaceutical compositions, and pharmaceutical products. Other features of the invention will become apparent from the dependent claims and the following description.

[0037] Unless otherwise stated, the following terms used in the specification and claims have the meanings described below.

[0038] The terms "comprising" or "including" mean including the specified components, but do not exclude the presence of other components. The terms "mainly composed of" or "consistently made of" mean including the specified components, but excluding other components, except for substances present as impurities, substances unavoidably present as a result of the process used to provide the components, and components added for purposes other than achieving the technical effects of the invention. The term "composed of" means including the specified components, but excluding other components.

[0039] Where appropriate, and depending on the context, the use of the terms “including” or “comprising” may also be understood to include the meaning of “mainly composed of” or “primarily composed of”, and may also be understood to include the meaning of “composed of”.

[0040] The optional features described herein can be used individually or in combination with each other where appropriate, particularly in the combinations described in the appended claims. Optional features of the various aspects or exemplary embodiments of the invention described herein are also applicable to all other aspects or exemplary embodiments of the invention where appropriate. In other words, those skilled in the art, upon reading this specification, should recognize that the optional features described for each aspect or exemplary embodiment of the invention are interchangeable and combinable between different aspects and exemplary embodiments.

[0041] The term “treatment” includes prevention and relief of established symptoms of a disease or medical condition. Therefore, “treatment” of a disease or medical condition includes: (1) preventing or delaying the development of clinical symptoms of a disease or medical condition in a person who may have or is susceptible to the disease or medical condition but has not yet experienced or shown its clinical or subclinical symptoms; (2) suppressing a disease or medical condition, i.e., preventing, reducing or delaying the development of a disease or medical condition or its recurrence (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing a disease, i.e. causing the disease or medical condition or at least one of its clinical or subclinical symptoms to subside.

[0042] "Therapeutic effective amount" refers to the amount of a compound that, when administered to a mammal to treat a disease, is sufficient to achieve the therapeutic effect on that disease. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age and weight of the mammal to be treated.

[0043] The term "(C)" 1-6 "alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl and n-pentyl.

[0044] The term "halogen" refers to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine, with fluorine being the most preferred.

[0045] When a group is substituted, it can be substituted at any chemically possible site on the group that meets the requirements of atomic valence. The group can be substituted by one or more substituents, such as 1, 2, 3, or 4 substituents; optionally, a group may have 1 or 2 substituents. When there are two or more substituents, the substituents can be the same or different.

[0046] Substituents exist only at chemically possible positions, and those skilled in the art can determine which substitutions are chemically possible without excessive effort (through experiment or theory).

[0047] The phrase “compounds of the present invention” refers to those compounds disclosed herein, namely compounds of formula (I), including general formulas and specific compounds.

[0048] compound

[0049] This invention provides compounds of formula (I):

[0050]

[0051] Or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0052] X is N or CR 19

[0053] R 1 Selected from 4-7 membered saturated heterocycles containing N, optionally containing additional O, N, or S atoms, or an S(O)2 group, wherein the heterocycle optionally contains:

[0054] (iv) Ether bridge, or

[0055] (v) Connecting another 4-7 member N-containing saturated heterocycle to form a spirobicyclic group; or

[0056] (vi) is connected to another 3-6 member N-containing saturated heterocycle, such that each ring shares two atoms, wherein the saturated heterocycle optionally contains a C(O) group;

[0057] The monocyclic or bicyclic heterocycle is optionally substituted by 1-3 substituents, wherein the substituents are independently selected from NC(O)C. 1-6 Alkyl, H, N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, OH and OC 1-6 Alkyl, HC(O)C 1-6 Alkyl, halogen, and Ph.

[0058] R 2 Selected from

[0059] and

[0060] R 3 Is it H or NH2?

[0061] R 4 It is CF3, CF2CH2OH, CN

[0062] R 5 It is halogen

[0063] R 6 It is H

[0064] R 7 It is H

[0065] R 8 It is Ph, which is substituted at the ortho position by CH2NHCH3.

[0066] R 25 It is H, OCH3, F and CN

[0067] In a suitable implementation scheme, R 2 yes

[0068]

[0069] R 3 Is it H or NH2?

[0070] Preferably R 3 It is H

[0071] R 4 It is CF3, CF2CH2OH, CN

[0072] Preferably R 4 It's CF3

[0073] R 5 It is halogen

[0074] Preferably R 5 It is F

[0075] In another suitable implementation, R 2 yes

[0076]

[0077] R 6 It is H

[0078] R 7 It is H

[0079] R 8 It is Ph, which is substituted at the ortho position by CH2NHCH3.

[0080] Preferably, R 1 Selected from:

[0081] , , , , , , , , , , , , , ,

[0082]

[0083] and NR 17 R 18 ,

[0084] Appropriately, R 1 Selected from

[0085] and

[0086] in

[0087] R 10 Selected from NC(O)C 1-6 Alkyl, H, N(C) 1-6 Alkyl)(C 1-6 alkyl)

[0088] Appropriately R 10 Selected from NC(O)CH3, H, N(CH3)2

[0089] R 11 Selected from C 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, OH and OC 1-6 alkyl

[0090] Appropriately, R 11 Selected from CH3, C(O)CH3, CH2-OCH3, OH.

[0091] R 12 Selected from NHC(O)C 1-6 Alkyl, C 1-6 Alkyl, H

[0092] Appropriately R 12 Selected from NHC(O)CH3, CH3, H.

[0093] R 13 Selected from NHC(O)C 1-6 Alkyl, C 1-6 Alkyl, H

[0094] Appropriately R 13 Selected from NHC(O)CH3, CH3, H.

[0095] R14 Selected from halogens, OH, OC 1-6 Alkyl, H

[0096] Appropriately R 14 Selected from F, OH and H.

[0097] More suitable R 14 It is H

[0098] R 15 Selected from halogens, OH, OC 1-6 Alkyl, H

[0099] Appropriately R 15 Selected from F, OH and H.

[0100] The most suitable R 15 It is OH

[0101] R 16 Selected from C(O)C 1-6 alkyl

[0102] Appropriately R 16 Selected from C(O)CH3

[0103] R 17 Selected from C 1-6 Alkyl, H, Ph

[0104] Appropriately R 17 Selected from CH3, H and Ph

[0105] R 18 Selected from C 1-6 Alkyl, H, Ph

[0106] Appropriately R 18 Selected from CH3, H and Ph

[0107] R 19 Selected from C(O)C 1-6 alkyl

[0108] Appropriately R 19 Selected from C(O)CH3

[0109] R 20 It is OH

[0110] R 21 Selected from C 1-6 Alkyl or H

[0111] Appropriately R 21 Selected from CH3 or H

[0112] R 22 Selected from C 1-6 Alkyl, H, C(O)C 1-6Alkyl groups and C(O)NHC 1-6 alkyl

[0113] Appropriately R 22 Selected from CH3, H, C(O)CH3 and C(O)NHCH3

[0114] R 23 Selected from C 1-6 Alkyl and H

[0115] Appropriately R 23 Selected from CH3 and H

[0116] R 24 It is C(O)C 1-6 alkyl

[0117] Appropriately R 24 It is C(O)CH3

[0118] In one implementation scheme R 21 and R 23 It is CH3, and R 22 It is H

[0119] In one implementation scheme R 21 and R 23 It is H, and R 22 It is C(O)NHCH3

[0120] In one implementation scheme R 21 and R 23 It is CH3, and R 22 It is CH3

[0121] In one implementation scheme R 21 It is CH3, R 23 It is H, and R 22 It is C(O)CH3

[0122] In a particularly suitable implementation, R 1 Selected from

[0123] and

[0124] Where R 14 It is H, R 15 It is OH

[0125] In a suitable implementation, X is N or CR 25 , where R 25 It's H.

[0126] Suitable pharmaceutically acceptable salts of compounds of formula (I) are, for example, acid addition salts, such as those formed with hydrochloric acid, citric acid, tartaric acid, and fumaric acid (especially hydrochloric acid). Acid addition salts can be obtained, for example, by reacting a compound of formula (I) with a suitable acid (such as hydrochloric acid, citric acid, tartaric acid, and fumaric acid) using conventional methods.

[0127] Pharmaceutically acceptable salts can also be formed by reacting with a suitable acid or base, or by converting one salt of the compounds of the present invention into another salt through a suitable ion exchange column.

[0128] The preparation of pharmaceutically acceptable salts is usually carried out in solution. The resulting salt can be precipitated and collected by filtration, or it can be recovered by evaporating the solvent.

[0129] The compounds of formula (I) can form salts in situ under physiological conditions, for example when used as drugs.

[0130] It should be understood that compounds of formula (I) can exist in solvated or non-solvated forms, such as hydrated forms. This invention covers all pharmaceutically acceptable solvated forms.

[0131] It should be understood that, due to the presence of one or more asymmetric carbon atoms, certain compounds of formula (I) as defined herein may exist in an optically active or racemic form, and the present invention includes any such optically active or racemic form within its definition.

[0132] It should be understood that this invention relates to isotopically labeled (i.e., radiolabeled) compounds of formula (I). In such compounds, one or more atoms are replaced by atoms with atomic masses or mass numbers different from those commonly found in nature. Examples of radionuclides that may be included in the compounds of this invention include... 2 H (also written as "D" to represent deuterium), 3 H (also written as "T" to represent tritium) 11 C 13 C 14 C 15 O、 17 O、 18 O、 18 F, etc. The specific radionuclide used will depend on the specific application of the radiolabeled compound.

[0133] Some compounds of this invention may contain one or more chiral centers and therefore may exist in stereoisomer form. Stereoisomers can be separated using conventional techniques, such as chromatography or stepwise crystallization. Enantiomers can be separated by separating racemic mixtures, for example by stepwise crystallization, resolution, or HPLC. Diastereomers can be separated by utilizing the different physical properties of the diastereomers, for example by stepwise crystallization, HPLC, or rapid chromatography. Alternatively, specific stereoisomers can be prepared by chiral synthesis, from chiral starting materials under conditions that do not cause racemization or epimerization, by derivatization with chiral reagents, or by asymmetric catalytic synthesis. When separating specific stereoisomers, it is suitable to separate them substantially free of other stereoisomers, for example, containing less than 0%, such as less than 10%, particularly less than 5% by weight of other stereoisomers.

[0134] It should be understood that compounds of formula (I) may exhibit polymorphism, and this invention covers all such forms.

[0135] Compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof may be prepared by any method known to be suitable for the preparation of chemically related compounds. Such methods are provided as a further feature of the invention when used to prepare compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof, and are illustrated by the following representative process variations. The necessary starting materials are commercially available or may be prepared by an organic chemist within the scope of ordinary skill using standard organic chemistry procedures, for example, in combination with the following representative processes and accompanying examples.

[0136] The compound of formula (I) can be prepared according to the process in step 1:

[0137] General reaction process

[0138] The compounds of the present invention can be prepared using commercially available reagents and intermediates in the synthetic methods and reaction processes described herein, or using other reagents and conventional methods known to those skilled in the art.

[0139] For example, the intermediate used to prepare the compound of template I of the present invention can be prepared according to general reaction procedure I.

[0140] General Reaction Flowchart 1

[0141]

[0142] General reaction procedure 1 is an example of template I. Compound 2 reacts with acetamidine hydrochloride to give compound 3. Treatment with benzyl mercaptan 4 in the presence of palladium catalysis and a base gives 5. Treatment of 5 with a chlorinating agent such as POCl3 gives compound 6. Compound 6 reacts with a suitable amine (such as intermediate 7) via nucleophilic substitution or a metal-catalyzed reaction to give compound 8. 8 reacts with 1,3-dichloro-5,5-dimethylhydantoin to give sulfonyl chloride 9. Treatment of 9 with various secondary or primary nucleophilic amines gives title compound 1.

[0143] Process 2

[0144]

[0145] The desired benzylamine, represented by compound 7, can be prepared from an aromatic aldehyde such as compound 7a. A chiral thioimine 7b is then formed, which is subsequently reduced to give a mixture of diastereomers of compounds 7c and 7d, which can be separated. The desired diastereomer 7d is then taken to the next step for sulfonamide cleavage to give the title intermediate 7.

[0146] The compounds of this invention are suitable for use as pharmaceuticals.

[0147] The present invention also provides compounds of the present invention for the treatment of pain.

[0148] SOS1 inhibitors offer numerous advantages for pain management; they do not carry the addictive potential of opioids, and they demonstrate potent efficacy. They also do not exhibit the side effects common to tanezumab and other anti-NGF drugs, which are often unusable at therapeutically effective doses.

[0149] The SOS1 compounds of the present invention also benefit from the high selectivity of SOS1 inhibitors relative to other targets, thereby improving efficacy, enhancing safety and minimizing off-target effects that may become sources of side effects in patients.

[0150] Suitably, the SOS1 inhibitor of the present invention exhibits selectivity greater than or equal to 100-fold relative to one or more of the following targets: MEK1, MEK2, TrkA kinase, TrkB kinase, TrkC kinase, C-Raf, B-Raf, PI3 kinase, AKT, and ERK.

[0151] When determining whether the selectivity of the compounds of the present invention for SOS1 is more than 100 times higher than that for another target, the following determinations and methods can be used:

[0152] MEK 1 and 2 can be determined using a MEK assay kit (product code CS0490, Sigma, St. Louis, USA).

[0153] Trk receptor kinase activity can be determined as described in Wang et al., Curr Chem Genomics. 2008; 1: 27–33.

[0154] B-Raf can be measured using the B-Raf kinase assay kit (product code 17-359, Sigma, St. Louis, USA).

[0155] C-Raf can be measured using the BPS Bioscience Assay Kit (catalog number 79570, San Diego, CA 92121, USA).

[0156] PI3 kinase can be determined by the method described in Fry, Methods Mol Biol, 2009;462:345-62.

[0157] AKT can be measured using the Abcam Akt Kinase Activity Assay Kit (ab139436) (abcam plc, Cambridge, USA).

[0158] ERK can be measured using the Promega ERK2 kinase kit (catalog number V1961, Promega corporation, Madison, USA).

[0159] The PK (pharmacokinetic) properties of the compound make it particularly suitable for use in this invention.

[0160] The compound has good bioavailability, permeability, solubility, stability, and many other qualities associated with drug molecules.

[0161] Without being bound by theory, SOS1 inhibitors are believed to treat pain in the following ways.

[0162] Nerve growth factor (NGF) is a protein that binds to its receptor (TrkA), leading to the upregulation of genes involved in nociception. NGF is known to be a significant contributor to the development of chronic pain. The binding of NGF to TrkA and subsequent signal transduction ultimately result in the nuclear accumulation of diphosphorylated extracellular signal-regulated kinase (dppERKnuc) in neurons, upregulating pain genes, such as… Figure 1 As shown.

[0163] The levels of SOS1 and its downstream affected molecules, such as Ras, enter this cascade. Higher levels of SOS and RAS lead to higher levels of bRAF and MEK, resulting in the accumulation of diphosphorylated extracellular signal-regulated kinase (dppERKnuc) and thus higher levels of pain. Inhibiting this pathway controls the formation of RAS GTP. By reducing RAS GTP levels, pain is alleviated.

[0164] The compound is suitable for treating pain.

[0165] The compound provides a method for treating pain.

[0166] The term pain includes, but is not limited to: acute pain; chronic pain; inflammatory pain; nociceptive pain; neuropathic pain; hyperalgesia; anomalous pain; central pain; cancer pain; postoperative pain; visceral pain; musculoskeletal pain; cardiac or vascular pain; headache, including migraine; orofacial pain, including toothache; and back pain.

[0167] More specifically, the types of pain suitable for treatment include, but are not limited to:

[0168] (a) Acute pain and / or spontaneous pain,

[0169] (b) Chronic pain and / or persistent pain,

[0170] (c) Inflammatory pain, including arthritis pain, pain caused by osteoarthritis or rheumatoid arthritis, pain caused by inflammatory bowel disease, psoriasis, and eczema.

[0171] (d) Nociceptive pain,

[0172] (e) Neuropathic pain, including pain associated with diabetic neuropathy or postherpetic neuralgia.

[0173] (f) Hyperalgesia,

[0174] (g) Abnormal pain,

[0175] (h) Central pain, central post-stroke pain, pain caused by multiple sclerosis, pain caused by spinal cord injury, or pain caused by Parkinson's disease or epilepsy.

[0176] (i) Cancer pain

[0177] (j) Postoperative pain,

[0178] (k) Visceral pain, including digestive and non-digestive visceral pain, pain attributable to gastrointestinal (GI) disorders, pain caused by functional bowel disease (FBD), pain caused by inflammatory bowel disease (IBD), pain caused by dysmenorrhea, pelvic pain, cystitis, interstitial cystitis, or pancreatitis.

[0179] (l) Musculoskeletal pain, myalgia, fibromyalgia, spondylitis, seronegative (non-rheumatoid) arthropathy, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis, pyogenic myositis,

[0180] (m) Pain in the heart or blood vessels, attributed to angina, myocardial infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma, or skeletal muscle ischemia.

[0181] (n) Headache, including migraine, migraine with aura, migraine without aura, cluster headache, tension headache;

[0182] (o) Orofacial pain, including toothache, temporomandibular myofascial pain, or tinnitus, or

[0183] (p) Back pain, bursitis, menstrual pain, migraine, referred pain, trigeminal neuralgia, hypersensitivity, pain caused by spinal trauma and / or degeneration or stroke.

[0184] Treatment of pain includes, but is not limited to, preventing pain, improving pain, controlling pain, reducing the incidence of pain, or delaying the development or progression of pain.

[0185] Particularly suitable indications for pain include osteoarthritis and cancer pain.

[0186] In another implementation, the appropriate indication is osteoarthritis.

[0187] According to another aspect of the invention, compounds of the invention are provided for use separately, sequentially, or simultaneously in combination with a second pharmacologically active compound. Preferably, the combined second pharmacologically active compound may include, but is not limited to:

[0188] Opioid analgesics, such as morphine, heroin, hydromorphone, hydroxymorphone, levonorgestrel, levonorgestrel, methadone, meridine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefen, nalprofen, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, or pentazocine;

[0189] Nonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, diclofenac, diflusinal, etodoxacin, fenbufen, fenprofen, flubendiclofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketoroxyprofen, meclofenamic acid, meloxicam, nabumetone, naproxen, nimesulide, nitroflurprofen, oxalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tometidine, or zolpidem;

[0190] Barbiturate sedatives, such as amobarbital, alpratobarbital, sec-butylbarbital, butabital, methylphenobarbital, methadone, mesobarbital, pentobarbital, phenobartital, secobarbital, tabbital, theamylal, or thiopental.

[0191] Benzodiazepines with sedative effects, such as chlordiazepoxide, diazepam, flurazepam, lorazepam, oxazepam, temazepam, or triazolam;

[0192] H1 antagonists with sedative effects, such as diphenhydramine, mepiquat, promethazine, chlorpheniramine, or chlorcyclorhizine;

[0193] Sedatives, such as glumethoxazole, meprobamate, methylquinalone, or chlorpyrifos;

[0194] Skeletal muscle relaxants, such as baclofen, cariporide, chlorzoxazone, cyclobenzapine, mesobamo, or olphenadrine;

[0195] NMDA receptor antagonists, such as dextromethorphan ((+)-3-hydroxy-N-methylmorphin) or its metabolite dextromethorphan ((+)-3-hydroxy-N-methylmorphin), ketamine, memantine, pyrroloquinolinequinine, cis-4-(phosphonomethyl)-2-piperidinic acid, budesonide, EN-3231 (MorphiDex®, a combination of morphine and dextromethorphan), topiramate, neramexane, or perzinfotel, including NR2B antagonists, such as afenidil, traxoprodil, or (-)-(R)-6-{2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone;

[0196] Alpha-adrenergic drugs, such as doxazosin, tamsulosin, clonidine, guanfasin, dexmetatomidine, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methanesulfinylamino-1,2,3,4-tetrahydroisoquinoline-2-yl)-5-(2-pyridyl)quinazoline;

[0197] Tricyclic antidepressants, such as desipramine, imipramine, amitriptyline, or nortriptyline;

[0198] Anticonvulsants, such as carbamazepine, lamotrigine, topiratmate, or valproate;

[0199] Tachykinin (NK) antagonists, particularly NK-3, NK-2, or NK-1 antagonists, such as (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazacyclic octatetraen[2,1-g][1,7]-naphthyl-6-13-dione (TAK-637), 5-[[(2R,3S) -2-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869), aprepitant, lanepitant, dapitant, or 3-[[2-methoxy-5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S);

[0200] Muscarinic antagonists, such as oxybutynin, tolterodine, propivelin, tropsium chloride, dafenapyr, solifenacin, telmivelin, and isoprazorpine;

[0201] COX-2 selective inhibitors, such as celecoxib, roficoxib, parecoxib, vardicoxib, delacoxib, etorcoxib, or rumicoxib;

[0202] Coal-tar analgesics, especially acetaminophen;

[0203] Tranquilizers, such as fluperidone, chlorpromazine, haloperidol, perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, serindole, aripiprazole, sonepiprazole, buspirone, ipraprazole, perropirone, racloprid, zolpidem, bifenproxol, asenapine, lurasidone, amisulpride, balaperidone, palindore, elixerin, oxanenetan, rimonaban, meclinertant, Miraxion®, or salizotan;

[0204] Vanillin receptor agonists (e.g., resinferatoxin) or antagonists (e.g., capsazepine);

[0205] Beta-adrenergic drugs, such as propranolol;

[0206] Local anesthetics, such as mexiletine;

[0207] Corticosteroids, such as dexamethasone;

[0208] 5-HT receptor agonists or antagonists, especially 5-HT 1B / 1D Agonists, such as iletriptan, sumatriptan, naratriptan, zolmitriptan, or rizatriptan;

[0209] 5-HT 2A Receptor antagonists, such as R(+)-α-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);

[0210] Cholinergic (nicotine) analgesics, such as ispronicline (TC-1734), (E)-N-methyl-4-(3-pyridyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azacyclobutylmethoxy)-2-chloropyridine (ABT-594), or nicotine;

[0211] Tramadol®;

[0212] PDEV inhibitors, such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazolo[2′,1′:6,1]pyrido[3,4] [b]Indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridyl)-3-ethyl-2-(1-ethyl-3-azacyclobutane)-2,6-dihydro-7 H-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyridyl)-3-ethyl-2-(1-isopropyl-3-azacyclobutane)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[2-methoxyethyl]-2,6-dihydro-7H-pyrazolo[ 4,3-d]pyrimidin-7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidin-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide;

[0213] cannabinoids;

[0214] Metabolic glutamate subtype 1 receptor (mGluR1) antagonists;

[0215] Serotonin reuptake inhibitors, such as sertraline, sertraline metabolite demethylsertraline, fluoxetine, norfluoxetine (fluoxetine demethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite demethylcitalopram, etapiprom, d,l-fenfluramine, fenmoxetine, ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, ciprochloramine, and trazodone;

[0216] Norepinephrine (norepinephrine) reuptake inhibitors, such as maprotiline, lofepramine, mirtazapine, oxyprotein, fezopramine, atomoxetine, mianserin, bupropion, bupropion metabolite hydroxybupropion, nomiphensine, and veloxacin (Vivalan®), especially selective norepinephrine reuptake inhibitors, such as reboxetine, particularly (S,S)-reboxetine;

[0217] Dual serotonin-norepinephrine reuptake inhibitors, such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, mirtazapine, and imipramine.

[0218] Inducible nitric oxide synthase (iNOS) inhibitors, such as S-[2-[(1-iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-L-cysteine, S-[2-[(1-iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2-amino-2-methyl-7-[(1-iminoethyl)amino]-5-heptenic acid, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)-butyl]thio]-5-chloro-3-pyridinecarboxylate; 2-[[(1R (3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, (2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl]thio]-5-thiazolylbutanol, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridinecarboxynitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3-chlorobenzylamino)ethyl]phenyl]thiophene-2-formamidinium or guanidinylethyl disulfide;

[0219] Acetylcholinesterase inhibitors, such as donepezil;

[0220] Prostaglandin E2 subtype 4 (EP4) antagonists, such as N-[({2-[4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide or 4-[(1S)-1-({[5-chloro-2-(3-fluorophenoxy)pyridin-3-yl]carbonyl}amino)ethyl]benzoic acid;

[0221] Leukotriene B4 antagonists; such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-5E-hexenyl]oxyphenoxy]valerate (ONO-4057) or DPC-11870;

[0222] 5-Lipooxidase inhibitors, such as zilutone, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl), 1,4-benzoquinone (CV-6504);

[0223] Sodium channel blockers, such as lidocaine; or

[0224] 5-HT3 antagonists, such as ondansetron;

[0225] And its pharmaceutically acceptable salts and solvates.

[0226] In another embodiment of the invention, it has been found that SOS1 inhibitors are particularly suitable for the treatment of pain when administered in combination with anti-NGF antibodies.

[0227] This invention provides a method for treating pain by administering a combination of a therapeutically effective amount of the compound of this invention and an anti-NGF antibody.

[0228] Tanezumab is an example of an anti-NGF antibody. It is a promising and effective treatment for pain, but at dose levels sufficient to provide pain relief, patients often suffer unpleasant side effects.

[0229] This combination provides synergistic efficacy, with the advantage that the anti-NGF antibody can be administered at a dose level sufficient to provide pain relief without reaching levels where adverse events can be observed. In the synergistic system, the two independent drugs are able to exhibit activity levels equivalent to one of the drugs at much higher doses. It is surprising that the combination of these two drugs has such an effect.

[0230] It is possible to reduce the dosage of tanizumab in humans and thus reduce the tendency to limit the use of this type of drug due to side effects. Compared with higher doses of tanizumab alone, the combination of SOS1 inhibition and NGF blockade via monoclonal antibodies such as tanizumab will deliver increased pain efficacy and reduced side effects.

[0231] Combinations of SOS1 inhibitors with NGF monoclonal antibodies or other NGF pathway blockers / modulators have the potential to provide greater pain relief and reduce side effects, thereby improving and enhancing the treatment of pain in diseases such as osteoarthritis.

[0232] Therefore, the present invention provides the use of the compounds of the present invention in combination with anti-NGF drugs, wherein one or both components are administered at a subtherapeutic dose to treat pain.

[0233] The term subtherapeutic dose is used to describe doses that are lower than the doses at which the component is shown to be effective as a single therapy.

[0234] Other advantages of this combination include the potential for oral administration instead of intravenous or subcutaneous administration. This combination can also result in lower treatment costs and provide a lower risk of immunogenicity.

[0235] Particularly suitable anti-NGF antibodies include tanizumab, fasinumab, fulranumab, and... MEDI735 .

[0236] The most suitable anti-NGF antibodies are tannicillin and fasinumab.

[0237] In a particularly preferred embodiment, the present invention provides the use of a combination of the compound of the invention with a subtherapeutic dose of tanizumab for the treatment of pain. Optionally, both the compound of the invention and tanizumab are administered at a subtherapeutic dose.

[0238] Compounds known as SOS1 inhibitors are effective in treating cancer. This invention provides compounds of the present invention for treating cancer. The compounds also provide a method for treating cancer.

[0239] Suitable cancers include pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, bladder epithelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, kidney cancer, and sarcoma.

[0240] In another respect, suitable cancers are selected from pancreatic cancer, lung cancer (preferably non-small cell lung cancer (NSCLC)), bile duct cancer, and colorectal cancer.

[0241] In another aspect, the present invention provides an SOS1 inhibitor of formula (I) for use in conditions selected from RASopathy, preferably selected from neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple freckles (NSML) (also known as LEOPARD syndrome), capillary malformation-arteriovenous malformation syndrome (CM-AVM), Costello syndrome (CS), cardiofacial-skin syndrome (CFC), Legius syndrome (also known as NF1-like syndrome), and hereditary gingival fibromatosis.

[0242] In another aspect, the diseases / symptoms / cancers for which the compounds of the present invention are intended to treat / prevent are defined as diseases / symptoms / cancers exhibiting one or more of the following molecular characteristics:

[0243] 1. KRAS changes:

[0244] a. KRAS amplification (wild-type or mutant);

[0245] b. KRAS overexpression (wild-type or mutant);

[0246] c. KRAS mutation:

[0247] i. G12 mutations (e.g., G12C, G12V, G12S, G12A, G12V, G12R, G12F,

[0248] G12D);

[0249] ii. G13 mutations (e.g., G13C, G13D, G13R, G13V, G13S, G13A) iii. T35 mutations (e.g., T35I);

[0250] iv. 136 mutations (e.g., I36L, I36M);

[0251] v. E49 mutation (e.g., E49K);

[0252] vi. Q61 mutations (e.g., Q61 H, Q61 R, Q61 P, Q61 E, Q61 K, Q61 L, Q61 K);

[0253] vii. K1 17 mutation (e.g., K1 17N);

[0254] viii. A146 mutations (e.g., A146T, A146V);

[0255] NRAS changes:

[0256] a. NRAS amplification (wild-type or mutant);

[0257] b. NRAS overexpression (wild-type or mutant);

[0258] c. NRAS mutation:

[0259] G12 mutations (e.g., G12A, G12V, G12D, G12C, G12S, G12R); G13 mutations (e.g., G13V, G13D, G13R, G13S, G13C, G13A); Q61 mutations (e.g., Q61K, Q61L, Q61H, Q61P, Q61R);

[0260] iv. A146 mutations (e.g., A146T, A146V);

[0261] HRAS changes:

[0262] a. HRAS amplification (wild-type or mutant);

[0263] b. HRAS overexpression (wild-type or mutant);

[0264] c. HRAS mutation;

[0265] i. G12 mutations (e.g., G12C, G12V, G12S, G12A, G12V, G12R, G12F, G12D);

[0266] ii. G13 mutations (e.g., G13C, G13D, G13R, G13V, G13S, G13A);

[0267] iii. Q61 mutations (e.g., Q61 K, Q61 L, Q61 H, Q61 P, Q61 R);

[0268] EGFR changes:

[0269] a. EGFR amplification (wild-type or mutant);

[0270] b. EGFR overexpression (wild-type or mutant);

[0271] c. EGFR mutation

[0272] i. For example, exon 20 insertion, exon 19 deletion (Del19), G719X (e.g., G719A, G719C, G719S), T790M, C797S, T854A, L858R, L861Q or any combination thereof;

[0273] ErbB2 (Her2) changes:

[0274] a. ErbB2 amplification;

[0275] b. ErbB2 overexpression; c. ErbB2 mutation

[0276] i. For example, R678, G309, L755, D769, D769, V777, P780, V842, R896, c.2264_2278del(L755_T759del), c.2339_2340ins(G778_P780dup), S310;

[0277] 6. c-MET changes:

[0278] a. c-MET amplification;

[0279] b. c-MET overexpression;

[0280] c. c-MET mutation

[0281] i. For example, E168, N375, Q648, A887, E908, T1010, V1088, H1112, R1166, R1188, Y1248, Y1253, M1268, D1304, A1357, P1382;

[0282] 7. AXL Changes:

[0283] a. AXL amplification;

[0284] b. AXL overexpression;

[0285] 8. BCR-ABL changes:

[0286] a. Chromosomal rearrangements involving the ABL gene;

[0287] 9. ALK changes:

[0288] a. ALK amplification;

[0289] b. ALK overexpression;

[0290] c. ALK mutation

[0291] i. For example, 1 151Tins, L1 152R, C1 156Y, F1 174L, L1 196M, L1 198F, G1202R, S1206Y, G1269A;

[0292] d. Chromosomal rearrangements involving the ALK gene;

[0293] 10. FGFR1 changed:

[0294] a. FGFR1 amplification;

[0295] b. FGFR1 overexpression;

[0296] 11. FGFR2 changed:

[0297] a. FGFR2 amplification;

[0298] b. FGFR2 overexpression;

[0299] 12. FGFR3 changed:

[0300] a. FGFR3 amplification;

[0301] b. FGFR3 overexpression;

[0302] c. Chromosomal rearrangements involving the FGFR3 gene; 13. NTRK1 alterations:

[0303] a. Chromosomal rearrangements involving the NTRK1 gene;

[0304] 14. NF1 Changes:

[0305] a. NF1 mutation;

[0306] 15. RET changes:

[0307] a. RET amplification;

[0308] b. RET overexpression;

[0309] c. Chromosomal rearrangements involving the RET gene

[0310] 16. ROS1 Changes:

[0311] a. ROS1 amplification;

[0312] b. ROS1 overexpression;

[0313] c. ROS1 mutation

[0314] i. For example, G2032R, D2033N, L2155S;

[0315] d. Chromosomal rearrangements involving the ROS1 gene; 17. SOS1 alterations

[0316] a. SOS1 amplification;

[0317] b. SOS1 overexpression;

[0318] c. SOS1 mutation;

[0319] 18. RAC1 changes

[0320] a. RAC1 amplification;

[0321] b. RAC1 overexpression;

[0322] c. RAC1 mutation;

[0323] 19. MDM2 Changes

[0324] a. MDM2 amplification

[0325] b. MDM2 overexpression

[0326] c. MDM2 amplification combined with functional p53 d. MDM2 amplification combined with wild-type p53

[0327] 20. RAS wild type

[0328] a. KRAS wild type

[0329] a. HRAS wild type

[0330] b. N RAS wild type. Particularly preferred are the SOS1 inhibitor compounds for use as defined herein (above and below), SOS1 inhibitor compounds for application, compounds of formula (I), compounds of formula (I) for application, uses for preparation, and methods for treatment and / or prevention of cancers treated / prevented, selected from:

[0331] Lung adenocarcinoma carrying KRAS mutations selected from G12C, G12V, G12D, and G12R;

[0332] Colorectal adenocarcinoma carrying KRAS mutations selected from G12D, G12V, G12C, G12R, and G13D; and

[0333] Pancreatic adenocarcinoma carrying KRAS mutations selected from G12D, G12V, G12R, G12C, and Q61H.

[0334] According to another aspect of the invention, compounds of the invention are provided for use in combination with a second pharmacologically active compound, alone, sequentially, or simultaneously. Preferably, the second pharmacologically active compound in the combination may include, but is not limited to, the following:

[0335] 1. Inhibitors of EGFR and / or its mutants

[0336] a. For example, afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, olmutinib, and EGF-816; b. Afatinib, osimertinib, and cetuximab are preferred.

[0337] c. The optimal choice is afatinib.

[0338] 2. Inhibitors of ErbB2 (Her2) and / or its mutants

[0339] a. For example, afatinib, lapatinib, trastuzumab, and pertuzumab;

[0340] b. Afatinib and trastuzumab are preferred.

[0341] c. Trastuzumab is the optimal choice;

[0342] 3. Inhibitors of ALK or its mutants

[0343] a. For example, crizotinib, alectinib, entrectinib, and brigatinib;

[0344] b. Crizotinib and alectinib are preferred;

[0345] c. Crizotinib is the preferred choice;

[0346] 4. Inhibitors of MEK or its mutants

[0347] a. For example, trametinib, cobimetinib, binimetinib, selumetinib, and refametinib;

[0348] b. Trametinib and Cobimetinib are preferred;

[0349] c. Trametinib is the preferred choice;

[0350] 5. Inhibitors of KRAS G12C

[0351] a. For example, ARS-853 (compound V-64 in WO 2014 / 152588), Example I-272 in WO 2016 / 044772;

[0352] 6. Inhibitors of BCR-ABL or its mutants

[0353] a. For example, imatinib, dasatinib, and nilotinib;

[0354] b. Imatinib and nilotinib are preferred;

[0355] c. Imatinib is the optimal choice;

[0356] 7. Inhibitors of FGFR1 and / or FGFR2 and / or FGFR3 or their mutants

[0357] a. For example, nintedanib;

[0358] 8. Inhibitors of ROS1 or its mutants

[0359] a. For example, crizotinib, entrectinib, lorlatinib, ceritinib, and merestinib;

[0360] b. Crizotinib and entrectinib are preferred;

[0361] c. Crizotinib is the preferred choice;

[0362] 9. Inhibitors of c-MET or its mutants

[0363] 10. Inhibitors of AXL or its mutants

[0364] 11. Inhibitors of NTRK1 or its mutants 12. Inhibitors of RET or its mutants

[0365] 13. Taxanes

[0366] a. For example, paclitaxel, nab-paclitaxel, and docetaxel;

[0367] b. Paclitaxel is preferred;

[0368] 14. Platinum-containing compounds

[0369] a. For example, cisplatin, carboplatin, and oxaliplatin;

[0370] 15. Antimetabolites

[0371] a. For example, combinations of 5-fluorouracil, capecitabine, fluorouracil, cytarabine, gemcitabine, trifluridine, and tipiracil (= TAS102);

[0372] b. Gemcitabine is preferred;

[0373] 16. Mitotic kinase inhibitors

[0374] a. For example, CDK4 / 6 inhibitors

[0375] For example, palbociclib, ribociclib, and abemaciclib;

[0376] Palbocicini and Abecicini are preferred.

[0377] iii. The preferred choice is abecini;

[0378] 17. Immunotherapy agents

[0379] a. For example, immune checkpoint inhibitors

[0380] i. For example, anti-CTLA4 mAb, anti-PD1 mAb, anti-PD-mAb, anti-PD-L2 mAb, anti-LAG3 mAb, and anti-TIM3 mAb;

[0381] ii. Preferably, it is anti-PD1 mAb;

[0382] iii. For example, ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, pidilizumab, and PDR-001 (BAP049-Clone-E disclosed and used in WO 2017 / 019896);

[0383] iv. Nivolumab, pembrolizumab, and PDR-001 are preferred.

[0384] v. The preferred choice is pembrolizumab;

[0385] 18. Anti-angiogenic drugs

[0386] a. For example, bevacizumab and nintedanib;

[0387] b. Bevacizumab is the preferred choice;

[0388] 19. Topoisomerase inhibitors

[0389] a. For example, irinotecan, liposomal irinotecan, and topotecan;

[0390] b. Irinotecan is the preferred choice;

[0391] 20. Inhibitors of A-Raf and / or B-Raf and / or C-Raf or their mutants, such as RAF-709 (Example 131 in WO 2014 / 151616) and LY-3009120 (Example 1 in WO 2013 / 134243);

[0392] 21. Inhibitors of ERK or its mutants

[0393] a. For example, ulixertinib;

[0394] 22. Apoptosis regulators

[0395] a. For example, inhibitors of the interaction between p53 (preferably functional p53, most preferably wild-type p53) and MDM2 (“MDM2 inhibitors”);

[0396] i. For example, HDM-201, NVP-CGM097, RG-71 12, MK-8242, RG-7388, SAR405838, AMG-232, DS-3032, RG-7775, APG-1 15;

[0397] ii. Preferably, HDM-201, RG-7388 and AMG-232 are used.

[0398] b. For example, PARP inhibitors;

[0399] c. For example, MCL-1 inhibitors;

[0400] 23. Inhibitors of mTOR

[0401] a. For example, rapamycin, temsirolimus, everolimus, and ridaforolimus;

[0402] 24. Epigenetic regulators

[0403] a. For example, BET inhibitors

[0404] i. For example, JQ-1, GSK 525762, OTX 015 (= MK8628), CPI 0610, TEN-010 (= RO6870810);

[0405] b. For example, CDK9 inhibitors;

[0406] 25. Inhibitors of IGF1 / 2 and / or IGF1-R

[0407] a. For example, xentuzumab (antibody 60833 in WO 2010 / 066868), MEDI-573 (=dusigitumab);

[0408] In this invention, it should be understood that the combinations, compositions, kits, methods, uses, or compounds for use according to the invention may be conceived to be applied simultaneously, in parallel, sequentially, successively, alternately, or individually to the active ingredients or components.

[0409] Literature data suggests that integrin and Aβ1-42 RAS / ERK signaling may be associated with tau protein hyperphosphorylation, focal adhesion formation, and other neuropathologies in Alzheimer's disease. Consistent with this, inhibitors of this pathway, such as MEK inhibitors, have been shown to improve neuropathological outcomes in cellular disease models. Furthermore, the risk ratio for AD is significantly increased in patients with neurofibromatosis (a disease caused by excessive signaling via SOS / RAS / ERK). Therefore, SOS1 inhibitors, which inhibit MEK in the same pathway, may also provide benefits in Alzheimer's disease and other dementias, offering additional therapeutic and safety profiles.

[0410] The compounds of the present invention can also be used to treat dementia, including:

[0411] Alzheimer's disease, mild cognitive impairment (MCI), Creutzfeldt-Jakob disease (CJD), Lewy body dementia (DLB), vascular dementia, alcohol-related brain injury (ARBD), early-onset dementia, frontotemporal dementia (FTD), and HIV-related cognitive impairment.

[0412] Alzheimer's disease includes mild Alzheimer's disease, moderate Alzheimer's disease, severe Alzheimer's disease, inflammatory Alzheimer's disease, non-inflammatory Alzheimer's disease, cortical Alzheimer's disease, early-onset Alzheimer's disease, and late-onset Alzheimer's disease.

[0413] Various literature studies indicate that the MAPK signaling pathway contributes to Parkinson's disease-related pathological processes, such as oxidative stress, neuroinflammation, autophagy, and neuronal death. Furthermore, MEK inhibitors have shown important neuroprotective properties upstream of dopaminergic neuronal apoptosis. It is anticipated that SOS1 inhibitors, which inhibit MEK in the same pathway, may also possess neuroprotective properties, with enhanced potency and safety compared to MEK inhibitors.

[0414] The compounds of this invention can also be used to treat Parkinson's syndrome, also known as Parkinson's disease. This includes idiopathic Parkinson's disease, vascular Parkinson's syndrome (also known as arteriosclerotic Parkinson's syndrome), drug-induced Parkinson's syndrome, multiple system atrophy, progressive supranuclear palsy, normal pressure hydrocephalus, tremor (including idiopathic tremor), and Wilson's disease.

[0415] The compounds of this invention can also be used to treat neurofibromatosis. Suitablely, neurofibromatosis is neurofibromatosis type 1.

[0416] The present invention also provides pharmaceutical formulations comprising a compound of formula I as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent, or carrier. The pharmaceutical formulation may further comprise one or more additional active agents for treating the aforementioned disorders.

[0417] The present invention also provides a medicament kit comprising a compound of formula I as defined above or a pharmaceutically acceptable salt or solvate thereof, and one or more additional active agents, as a combination formulation for separate, simultaneous or sequential administration in the treatment of the above-described conditions.

[0418] The present invention also provides a method for treating the aforementioned conditions in mammals (especially humans), the method comprising administering to the mammal requiring the treatment a therapeutically effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt or solvate thereof.

[0419] The compounds of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous products. They can be obtained, for example, as solid plugs, powders, or membranes by methods such as precipitation, crystallization, freeze-drying, spray drying, or evaporative drying. Microwave or radio frequency drying can be used for this purpose.

[0420] They can be administered alone or in combination with one or more other compounds of the present invention or with one or more other drugs (or as any combination thereof). Typically, they will be administered as a formulation in combination with one or more pharmaceutically acceptable excipients. The term "excipient" is used herein to describe any ingredient other than the compounds of the present invention. The selection of excipients will depend heavily on a variety of factors, such as the specific administration method, the effect of the excipient on solubility and stability, and the nature of the dosage form.

[0421] Pharmaceutical compositions suitable for delivering the compounds of the present invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods of preparation can be, for example... Remington's Pharmaceutical Sciences It can be found in the 19th edition (Mack Publishing Company, 1995).

[0422] Oral administration

[0423] The compounds of this invention can be administered orally. Oral administration may include swallowing, allowing the compound to enter the gastrointestinal tract, or it may be administered directly into the bloodstream through the mouth or sublingually.

[0424] Formulations suitable for oral administration include solid dosage forms, such as tablets, capsules containing granules, liquids or powders, lozenges (including liquid-filled ones), chewable tablets, multi-particle and nanoparticle formulations, gels, solid solutions, liposomes, films, beads, sprays and liquid formulations.

[0425] Liquid formulations include suspensions, solutions, syrups, and elixirs. These formulations can be used as fillers in soft or hard capsules and typically contain a carrier such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, as well as one or more emulsifiers and / or suspending agents. Liquid formulations can also be prepared by reconstructing a solid, such as a solid derived from a small capsule.

[0426] The compounds of the present invention can also be used in rapidly dissolving and rapidly disintegrating formulations, such as those described in Liang and Chen's Expert Opinion in Therapeutic Patents, 11 (6), 981-986, (2001).

[0427] For tablet dosage forms, depending on the dosage, the drug can comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight. In addition to the drug, tablets usually contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will comprise 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0428] Binders are commonly used to impart cohesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate.

[0429] The tablets may also optionally contain surfactants, such as sodium lauryl sulfate and polysorbate 80, and gliding agents, such as silica and talc. When present, the surfactants may comprise 0.2% to 5% by weight of the tablets, and the gliding agents may comprise 0.2% to 1% by weight of the tablets.

[0430] Tablets typically also contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, and mixtures of magnesium stearate and sodium dodecyl sulfate. The lubricant typically constitutes 0.25% to 10% by weight of the tablet, preferably 0.5% to 3% by weight.

[0431] Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents.

[0432] An exemplary tablet contains up to about 80% of the drug, about 10% to about 90% of the binder, about 0% to about 85% of the diluent, about 2% to about 10% of the disintegrant and about 0.25% to about 10% of the lubricant.

[0433] Tablet mixtures can be directly compressed or rolled into tablets. Alternatively, tablet mixtures or portions thereof can be wet-granulated, dry-granulated, melt-granulated, melt-coated, or extruded before tableting. The final formulation may contain one or more layers and may be coated or uncoated; it may even be encapsulated.

[0434] The tablet formulation was developed by H. Lieberman and L. Lachman. Pharmaceutical Dosage Forms: Tablets This is discussed in Volume 1 (Marcel Dekker, New York, 1980).

[0435] Consumable oral films for human or veterinary use are typically flexible, water-soluble or water-swellable film formulations that dissolve rapidly or adhere to mucous membranes, and generally contain a compound of formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation may perform more than one function.

[0436] The compounds of the present invention can be water-soluble or insoluble. Water-soluble compounds typically comprise 1% to 80% by weight of the solute, more typically 20% to 50% by weight. Compounds with lower solubility can comprise a larger proportion of the composition, typically up to 88% by weight of the solute. Alternatively, the compounds of the present invention can be in the form of multi-particle beads.

[0437] The film-forming polymer can be selected from natural polysaccharides, proteins or synthetic hydrocolloids, and is typically present in the range of 0.01 to 99% by weight, and more typically in the range of 30 to 80% by weight.

[0438] Other possible ingredients include antioxidants, colorants, flavoring agents and flavor enhancers, preservatives, saliva stimulants, coolants, cosolvents (including oils), softeners, fillers, defoamers, surfactants, and masking agents.

[0439] The membranes according to the invention are typically prepared by evaporative drying of an aqueous film coated onto a peelable backing carrier or paper. This can be carried out in a drying oven or tunnel, typically a combined coating dryer, or by freeze drying or vacuum drying.

[0440] Solid dosage forms intended for oral administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0441] Modified release formulations suitable for the purposes of this invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies, such as high-energy dispersions and permeable and coated particles, can be found in Verma et al. Pharmaceutical Technology Online , 25(2), 1-14, (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298.

[0442] External application

[0443] The compounds of this invention can also be directly applied to the bloodstream, muscles, or internal organs. Suitable methods for parenteral administration include intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, and subcutaneous administration. Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors, and infusion techniques.

[0444] Parenteral preparations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably up to pH 3 to 9). However, for some applications, they may be more suitably formulated as sterile non-aqueous solutions or in dry form for use in combination with suitable carriers such as sterile, pyrogen-free water.

[0445] The preparation of parenteral preparations under aseptic conditions, such as by freeze-drying, can be easily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

[0446] The solubility of the compounds of the present invention used for preparing parenteral solutions can be improved by using appropriate formulation techniques, such as incorporating solubility enhancers.

[0447] Formulations intended for parenteral administration can be formulated to provide immediate release and / or altered release. Alternated release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release. Therefore, the compounds of the present invention can be formulated as solids, semi-solids, or thixotropic liquids for administration as implantable repositories, providing altered release of the active compound. Examples of such formulations include drug-coated scaffolds and poly(dl-glycolic acid-lactide copolymer) (PGLA) microspheres.

[0448] Topical application

[0449] The compounds of this invention can also be applied topically to the skin or mucous membranes, i.e., transdermal or transdermal. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, rice paper capsules, implants, sponges, fibers, bandages, and microemulsions. Liposomes may also be used. Typical carriers include alcohols, water, mineral oils, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Permeation enhancers may be incorporated—see, for example, Finnin and Morgan's J Pharm Sci. 88 (10), 955-958 (October 1999).

[0450] Other methods of local application include delivery via electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free injection (e.g., Powderject™, Bioject™, etc.).

[0451] Formulations intended for topical application can be formulated to provide immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0452] Inhalation / Nasal administration

[0453] The compounds of the present invention can also be administered intranasally or by inhalation, typically in the form of dry powder from a dry powder inhaler (alone, as a mixture, such as a dry mix with lactose, or as mixed component particles, such as a mixture with phospholipids like phosphatidylcholine) or as an aerosol spray from a pressurized container, pump, nebulizer, nebulizer (preferably using a nebulizer that generates a fine mist using electrohydrodynamics) or nebulized inhaler, with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin.

[0454] The pressurized container, pump, sprayer, nebulizer, or nebulizer inhaler contains a solution or suspension of the compounds of the present invention, said solution or suspension comprising, for example, ethanol, aqueous ethanol or alternative agents suitable for dispersing, dissolving or prolonging the release of the active substance, a propellant as a solvent, and optional surfactants such as sorbitan trioleate, oleic acid or oligolactic acid.

[0455] Before being used in the formulation of dry powders or suspensions, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 micrometers). This can be achieved by any suitable pulverization method, such as helical jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high-pressure homogenization, or spray drying.

[0456] Capsules (e.g., made of gelatin or hydroxypropyl methylcellulose), blisters, and cartridges for inhalers or blow-off devices can be formulated as powder mixtures containing the compounds of the present invention, a suitable powder matrix (e.g., lactose or starch), and a performance modifier (e.g., L-leucine, mannitol, or magnesium stearate). Lactose can be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0457] Solution formulations suitable for nebulizers that generate fine mist using electrohydrodynamics may contain 1 μg to 20 mg of the compound of the present invention per actuation, with an actuation volume varying from 1 μl to 100 μl. Typical formulations may contain a compound of formula I, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerol and polyethylene glycol.

[0458] Suitable flavoring agents (e.g., menthol and levmenthol) or sweeteners (e.g., saccharin or sodium saccharin) can be added to those formulations of the present invention intended for inhalation / nasal administration.

[0459] Formulations intended for inhalation / intranasal administration can be formulated using, for example, PGLA to provide immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0460] In the case of dry powder inhalers and aerosols, the dosage unit is determined by the valve that delivers the metering. Units according to the invention are generally arranged to administer a metered dose or “one spray” containing 1 to 10,000 μg of the compound of the invention. The total daily dose is typically in the range of 1 μg to 10 mg, which can be administered in a single dose throughout the day or more usually in split doses.

[0461] Rectal / vaginal application

[0462] The compounds of this invention can be administered rectally or vaginally, for example, in the form of suppositories, vaginal rings, or enemas. Cocoa butter is a conventional suppository base, but various alternatives can be used as needed.

[0463] Formulations intended for rectal / vaginal administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0464] Eye / ear application

[0465] The compounds of this invention can also be applied directly to the eye or ear, typically as drops of micronized suspensions or solutions in isotonic, pH-adjusted sterile saline. Other formulations suitable for eye and ear application include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, rice paper encapsulations, lenses, and particle or vesicle systems, such as vesicles or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulose polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose, or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum) can be incorporated with preservatives (e.g., benzalkonium chloride). These formulations can also be delivered via iontophoresis.

[0466] Formulations intended for ocular / otal administration can be formulated for immediate release and / or modified release. Modified release formulations include delayed release, sustained release, pulsatile release, controlled release, targeted release, or programmed release.

[0467] Other technologies

[0468] The compounds of the present invention can be combined with soluble macromolecular entities, such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability, for use in any of the above-described administration methods.

[0469] For example, it has been found that drug-cyclodextrin complexes are generally available for most dosage forms and routes of administration. Inclusion complexes and non-inclusion complexes can be used. As an alternative to direct compounding with drugs, cyclodextrins can be used as co-additives, i.e., as carriers, diluents, or solubilizers. The most commonly used for these purposes are α-, β-, and γ-cyclodextrins, examples of which can be found in international patent applications WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148.

[0470] Complete set of medicine boxes

[0471] Since it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a specific disease or condition, within the scope of this invention, two or more pharmaceutical compositions (at least one of which contains a compound of this invention) can be conveniently combined into a kit form suitable for co-administration of the composition.

[0472] Therefore, the pillbox of the present invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I according to the invention, and means for individually storing said compositions, such as a container, separate bottle, or separate foil pack. An example of such a pillbox is the familiar blister pack used for packaging tablets, capsules, etc.

[0473] The pillbox of this invention is particularly suitable for administering different dosage forms, such as oral and parenteral, for administering individual compositions at different dose intervals, or for gradually increasing the dosage of an individual composition relative to another. To aid compliance, the pillbox typically includes instructions for use and may provide so-called memory aids.

[0474] dose

[0475] For human patients, the total daily dose of the compounds of the present invention typically ranges from 0.5 mg to 3000 mg, depending on the method of administration. For example, oral administration may require a total daily dose of 3 mg to 3000 mg, while intravenous administration may require only 0.5 mg to 500 mg. The total daily dose may be administered as a single dose or in multiple doses and may fall outside the typical range given herein, depending on the physician's judgment.

[0476] These dosages are based on the average human individual weighing approximately 60 kg to 70 kg. Physicians will be able to easily determine the dosage for subjects whose weight exceeds this range (such as infants and the elderly).

[0477] To avoid ambiguity, the term "treatment" in this article includes terms for curative, palliative, and preventative treatment.

[0478] experiment

[0479] Materials and methods

[0480] The invention will now be illustrated by the following non-limiting embodiments, wherein unless otherwise stated... :

[0481] (i) Temperature is given in degrees Celsius (°C); operation is carried out at room temperature or ambient temperature, i.e., at a temperature in the range of 18 to 25°C;

[0482] (ii) The final product has satisfactory proton and carbon nuclear magnetic resonance (NMR) spectra and / or mass spectrometry data;

[0483] (iii) Yields are for illustrative purposes only and are not necessarily those that can be obtained through diligent process development; if more material is needed, the preparation should be repeated.

[0484] (iv) When given, NMR data are in the form of δ values ​​for the primary diagnostic proton, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using deuterated dimethyl sulfoxide (DMSO-d6) as solvent, unless otherwise specified; the following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; Bs, broad singlet; dd, doublet.

[0485] (v) Chemical symbols have their usual meanings; SI units and symbols are used.

[0486] The following is a list of abbreviations used in this invention:

[0487] ACN Acetonitrile

[0488] AcOH (acetic acid)

[0489] Aq contains water

[0490] BSA (Bovine Serum Albumin)

[0491] CS2CO3 cesium carbonate

[0492] DCM dichloromethane

[0493] DIPEA N,N-Diisopropylethylamine

[0494] DME dimethoxyethane

[0495] DMF (dimethylformamide)

[0496] DMF-DMA N,N-dimethylformamide dimethylacetal

[0497] DMSO (dimethyl sulfoxide)

[0498] DTT dithiothreitol

[0499] EDA-GTP-DY-647P1 273'-O-(2-aminoethyl-carbamoyl)-guanosine-5'-triphosphate DY-647Pl labeled triethylammonium salt

[0500] EtOAc (ethyl acetate)

[0501] EtOH (ethanol)

[0502] FRET fluorescence resonance energy transfer

[0503] GDP Guanosine diphosphate

[0504] GEF (Guinea Nucleotide Exchange Factor)

[0505] GTP (guanosine triphosphate)

[0506] HATU (l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[0507] HEPES (4-(2-hydroxyethyl)-l-piperazine ethanesulfonic acid)

[0508] HPLC (High Performance Liquid Chromatography)

[0509] HTRF homogeneous time-resolved fluorescence

[0510] IPA isopropanol

[0511] K2CO3 (potassium carbonate)

[0512] KRAS Kirsten rat sarcoma

[0513] KO l Potassium tert-butoxide

[0514] LC liquid chromatography

[0515] LiOH.H2O Lithium hydroxide monohydrate

[0516] MeOH (methanol)

[0517] MeONa sodium methoxide

[0518] MS mass spectrometry

[0519] NaBH4 sodium borohydride

[0520] NaNC Sodium Nitrite

[0521] NaIO4 Sodium periodate

[0522] NH4Cl ammonium chloride

[0523] NiCH ·6H2O Nickel(II) chloride hexahydrate

[0524] nM nanomolar

[0525] NMR (Nuclear Magnetic Resonance) spectroscopy

[0526] O / N overnight

[0527] Pd-C Palladium on Carbon

[0528] Pd(PPhs)4 tetrakis(triphenylphosphine)palladium(0)

[0529] POCI3 phosphoryl chloride

[0530] prep preparation

[0531] TEA Triethylamine

[0532] THF Tetrahydrofuran

[0533] TFA (trifluoroacetic acid)

[0534] TiCU titanium tetrachloride

[0535] TLC (Thin Layer Chromatography)

[0536] The following intermediates can be used to prepare the compounds of this invention.

[0538] Example 1: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,2-trimethylquinazole porphyrin-6-sulfonamide

[0539] Preparation 1: 6-Bromo-4-chloro-2-methylquinazoline

[0540]

[0541] To a stirred solution of 6-bromo-2-methylquinazoline-4(1H)-one (1 g, 4.18 mmol) dissolved in toluene (10 mL, 10 V), DIPEA (2.8 mL, 16.73 mmol) and POCl3 (3.9 mL, 41.84 mmol) were added. The resulting reaction mixture was stirred at 110°C for 6 hours. TLC (30% EtOAc / hexane) showed complete consumption of SM. The reaction mixture was diluted with saturated NaHCO3 solution (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography with elution of (26:74) ethyl acetate / hexane to give 6-bromo-4-chloro-2-methylquinazoline (0.6 g, 55.70%) as a creamy white solid.

[0542] LCMS tR (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.322 min, m / z = 257.0 [M+H] + .

[0543] 1H-NMR: (400 MHz, CDCl3): δ 8.40 (s, 1H), 8.01 (dd, J =2.4 Hz, 8.8 Hz, 1H), 8.86 (d, J =9.2 Hz, 1H), 2.86 (s, 3H).

[0545] Preparation 2: (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazolin-4-amine

[0546]

[0547] Potassium acetate (0.64 g, 6.59 mmol) was added to a stirred solution of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (0.29 g, 1.55 mmol) in ethanol (10 mL, 20 V) at room temperature, and the mixture was stirred for 15 minutes. Then, 6-bromo-4-chloro-2-methylquinazoline (0.5 g, 1.94 mmol) was added to the above reaction mixture, and the resulting mixture was stirred at 110°C for 4 hours. TLC (30% ethyl acetate / hexane) showed complete consumption of saturated solution. The resulting solution was concentrated under reduced pressure. The residue was purified by normal-phase chromatography, eluting with (26:74) ethyl acetate / hexane to give (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazoline-4-amine (0.4 g, 50.22%) as a creamy white solid.

[0548] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.057 min, m / z = 411.9 [M+2H] + .

[0549] 1H-NMR: (400 MHz, DMSO-d6): δ 8.73 (d, J = 2.00 Hz, 1H), 8.58 (d, J =7.20 Hz, 1H), 7.85 (dd, J = 2.40, 8.80 Hz, 1H), 7.69 (t, J = 7.20 Hz, 1H),7.55 (s, 1H), 7.51 (t, J = 6.80 Hz, 1H), 7.29 (t, J = 8.00 Hz, 1H), 7.24 (s,1H), 5.74-5.81 (m, 1H), 2.38 (s, 3H), 1.60 (d, J = 6.80 Hz, 3H).

[0551] Preparation 3: (R)-6-(benzylthio)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazoline- 4-amine

[0552]

[0553] DIPEA (0.2 g, 0.95 mmol) was added to a stirred solution of (R)-6-bromo-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazoline-4-amine (0.4 g, 0.97 mmol) and phenylmethanethiol (0.45 g, 1.17 mmol) in dioxane (4 mL, 10 V). The resulting solution was purged with N2 for 10 min. Xanthphos (0.11 g, 0.19 mmol) and Pd2(dba)3 (0.18 g, 0.19 mmol) were then added to the above reaction mixture, and the mixture was stirred at 100°C for 16 h. TLC (30% EtOAc / DCM) showed complete consumption of SM. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 50 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography by elution with (20:80) ethyl acetate / hexane to give (R)-6-(benzylthio)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazoline-4-amine (0.4 g, 90.46%), as a creamy white solid.

[0554] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.198 min, m / z = 454.0 [M+H] + .

[0555] Preparation 4: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazolin-6-sulfonate Acyl chloride

[0556]

[0557] Acetic acid (0.01 mL) and water (0.01 mL) were added to a stirred solution of (R)-6-(benzylthio)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylquinazoline-4-amine (0.4 g, 0.88 mmol) dissolved in acetonitrile (4 mL, 10 V). Then, 1,3-dichloro-5,5-dimethylhydantoin (0.87 g, 4.41 mmol) was added in portions to the above solution at 0°C. The resulting reaction mixture was stirred at 0°C for 1 hour. TLC (30% EtOAc / hexane) showed complete consumption of SM. The reaction mixture was diluted with saturated NaHCO3 solution (10 mL) and extracted with DCM (2 x 10 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline-6-sulfonyl chloride (0.4 g, quantitative), which was a yellow solid.

[0558] LCMS t R (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 1.351 min, m / z = not supported.

[0559] Example 1, Preparation of 5: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,2-tris( ... Methylquinazoline-6-sulfonamide

[0560]

[0561] TEA (0.1 mL, 0.69 mmol) was added to a stirred solution of dimethylamine (2 M, in THF) (0.13 mL, 0.28 mmol) in THF (0.5 mL). Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline-6-sulfonyl chloride (0.10 g, 0.23 mmol) in THF (1 mL, 10 V) was added dropwise to the above solution under a nitrogen atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (30% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (5 mL) and ethyl acetate (2 x 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,2-trimethylquinazoline-6-sulfonamide (0.01 g, 10.78%), which was a creamy white solid.

[0562] LCMS tR (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 1.927 min, m / z = 439.2 [M+H]+.

[0563] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 4.91 min.

[0564] 1H-NMR: (400 MHz, DMSO-d6): δ 9.08 (d, J =7.2 Hz, 1H), 8.95 (s, 1H),8.01-7.96 (m, 1H), 7.76(d, J =8.8 Hz, 1H), 7.69 (t, J =7.2 Hz, 1H), 7.51 (t, J =6.8 Hz, 1H), 7.30 (t, J =7.6 Hz, 1H), 7.25 (s, 1H), 5.84-5.80 (m, 1H), 2.66(s, 6H), 2.39 (s, 3H), 1.64 (d, J =7.2 Hz, 3H).

[0565] Example 2: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,2-trimethylpyridine [3,4-d]pyrimidine-6-sulfonamide

[0566] Preparation 1: 6-Chloro-2-methylpyrido[3,4-d]pyrimidin-4(1H)-one

[0567]

[0568] Sodium acetate (14.3 g, 174 mmol) was added to a solution of 5-amino-2-chloroisonicotinic acid (10 g, 58.1 mmol) and acetamidine hydrochloride (16.3 g, 174 mmol) in 2-methoxyethanol (1.2 L) at room temperature. The reaction mixture was stirred at 130°C for 48 hours. TLC (100% EtOAc) showed complete consumption of SM. The reaction mixture was concentrated under reduced pressure to remove 2-methoxyethanol. The residue was poured into water, and a brown solid precipitated. The precipitate was filtered, collected through a Buchner funnel, and dried under reduced vacuum to give 6-chloro-2-methylpyridano[3,4-d]pyrimidin-4(1H)-one (9.5 g, 83.81%) as a brown solid.

[0569] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 1.265 min, m / z = 195.2 [M+H] + .

[0570] 1H-NMR: (400 MHz, DMSO-d6): δ 12.69 (s, 1H), 8.83 (s, 1H), 7.94 (s,1H), 2.39 (s, 3H)

[0571] Preparation of 2: 6-(benzylthio)-2-methylpyrido[3,4-d]pyrimidin-4(1H)-one

[0572]

[0573] K₂CO₃ (10.61 g, 76.92 mmol) was added to a stirred solution of 6-chloro-2-methylpyrido[3,4-d]pyrimidin-4(1H)-one (5 g, 25.64 mmol) dissolved in DMF (50 mL, 10 V). Then, phenylmethanethiol (3.17 g, 25.64 mmol) was added to the reaction mixture, and the mixture was stirred at 100°C for 48 hours. TLC (90% EtOAc / DCM) showed complete consumption of SM. The reaction mixture was diluted with water (100 mL), and a solid precipitated. The precipitate was filtered, collected through a Buchner funnel, and dried under reduced pressure to give 6-(benzylthio)-2-methylpyrido[3,4-d]pyrimidin-4(1H)-one (5 g, 69.03%) as a creamy white solid.

[0574] LCMS t R(Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 1.997 min, m / z = 284.3 [M+H] + .

[0575] 1H-NMR: (400 MHz, DMSO-d6): δ 12.50 (s, 1H), 8.88 (s, 1H), 7.73 (s,1H), 7.44-7.42 (m, 2H), 7.33-7.30 (m, 2H), 7.26-7.23 (m, 1H), 4.48 (s, 2H),2.36 (s, 3H).

[0576] Preparation of 3:6-(benzylthio)-4-chloro-2-methylpyrido[3,4-d]pyrimidine

[0577]

[0578] DIPEA (1.84 mL, 10.60 mmol) and POCl3 (2.16 mL, 14.13 mmol) were added to a stirred solution of 6-(benzylthio)-2-methylpyrido[3,4-d]pyrimidin-4(1H)-one (2 g, 7.06 mmol) dissolved in toluene (20 mL, 10 V). The resulting reaction mixture was stirred at 110°C for 13 hours. TLC (70% EtOAc / hexane) showed complete consumption of SM. The reaction mixture was concentrated under reduced vacuum to give crude 6-(benzylthio)-4-chloro-2-methylpyrido[3,4-d]pyrimidin (2 g, 93.89%) as a brown, viscous solid.

[0579] Note: The crude product is used directly in the next step.

[0580] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.664 min, m / z = 302.1 [M+H]

[0581] Preparation 4: (R)-6-(benzylthio)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyridin [3,4-d]pyrimidin-4-amine

[0582]

[0583] DIPEA (3.5 mL, 19.9 mmol) was added to a stirred solution of (R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl-1-amine (1.25 g, 6.64 mmol) in THF (20 mL, 10 V) at room temperature, and the mixture was stirred for 15 minutes. Then, 6-(benzylthio)-4-chloro-2-methylpyridinidine[3,4-d]pyrimidine (2 g, 6.64 mmol) was added to the above reaction mixture, and the resulting mixture was stirred at 80°C for 3 hours. TLC (70% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic matter was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography by elution with (30:70) ethyl acetate / hexane to give (R)-6-(benzylthio)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine (1.5 g, 50%), as a brown solid.

[0584] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.335 min, m / z = 455.3 [M+H]

[0585] 1H-NMR: (400 MHz, DMSO-d6): δ 8.94 (s, 1H), 8.72 (d, J =7.2 Hz, 1H), 8.25 (s, 1H), 7.67 (t, J =7.6 Hz, 1H), 7.52 (t, J =6.8 Hz, 1H), 7.43-7.41 (m,2H), 7.32-7.10 (m, 5H), 5.78-5.74 (m, 1H), 4.51 (s, 2H), 2.38 (s, 3H), 1.60(d, J =6.8 Hz, 1H).

[0586] Preparation of 5: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4- d]Pyrimidine-6-sulfonyl chloride

[0587]

[0588] Add (R)-6-(benzylthio)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (1 g, 2.20 mmol) to a stirred solution of acetic acid (40 mL, 40 V) and water (10 mL, 10 V). Add in portions to the above solution at room temperature. N 1,55 g, 11.62 mmol of chlorosuccinimide was used. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% EtOAc / hexane) showed complete consumption of SM. The reaction mixture was diluted with saturated NaHCO3 solution (100 mL) and extracted with DCM (2 x 50 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (1.1 g, quantitative) as a yellow solid.

[0589] Note: The crude product is used directly in the next step.

[0590] LCMS t R (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 1.126 min, m / z = 413.12 (Acid mass observed).

[0591] Example 2 : Preparation of 6: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,2-tris( ... Methylpyrido[3,4-d]pyrimidine-6-sulfonamide

[0592]

[0593] TEA (0.1 mL, 0.69 mmol) was added to a stirred solution of dimethylamine (2 M, in THF) (0.20 mL, 0.42 mmol) in THF. Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.15 g, 0.34 mmol) in THF (3 mL, 10 V) was added dropwise to the above solution under a nitrogen atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (60% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (2 x 20 mL). The combined organic compounds were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography by elution with (32:68) ethyl acetate / hexane to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,N,2-trimethylpyridino[3,4-d]pyrimidine-6-sulfonamide (0.008 g, 5.23%), as a creamy white solid.

[0594] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.189 min, m / z = 440.3 [M+H]+.

[0595] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 6.336 min.

[0596] 1H-NMR: (400 MHz, DMSO-d6): δ 9.34 (d, J = 6.8 Hz, 1H), 9.07 (s, 1H),9.03 (s, 1H), 7.71(t, J =7.2 Hz, 1H), 7.53 (t, J =5.6 Hz, 1H), 7.32 (t, J =7.2Hz, 1H), 7.25 (s, 1H), 5.80-5.77 (m, 1H), 2.84 (s, 6H), 2.45 (s, 3H), 1.63(d, J =6.8 Hz 3H).

[0597] Example 3: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,2-dimethylquinazole porphyrin-6-sulfonamide

[0598]

[0599] Methylamine (2M, in THF) (0.23 mL, 0.46 mmol, 2.0 equivalence) was added to a stirred solution of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylquinazoline-6-sulfonyl chloride (0.1 g, 0.23 mmol) in DCM (10 V). The resulting mixture was stirred at room temperature for 1 hour. TLC (70% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (50 mL) and ethyl acetate (50 mL). The combined organic matter was dried over Na2SO4, filtered, and evaporated. The residue was purified by preparative HPLC by elution with 0.1% M.NH3 (50:50) in MEOH:CAN to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-N,2-dimethylquinazoline-6-sulfonamide (0.004 g, 4%), as a white solid.

[0600] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 1.859 min, m / z = 425 [M+H] +.

[0601] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 4.790 min.

[0602] 1 H NMR (400 MHz, DMSO): δ 9.06 (d, J = 7.0 Hz, 1H), 8.96 (d, J = 1.5Hz, 1H), 8.00 (dd, J = 8.8, 1.9 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.52 – 7.49 (m,2H), 7.38 – 7.24 (m, 2H), 5.82 (t, J = 7.1 Hz, 1H), 2.46(s, 3H), 2.38 (s,3H), 1.63 (d, J = 7.0 Hz, 3H).

[0603] Example 4: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyrrolidone-1-yl) (sulfonyl)pyrido[3,4-d]pyrimidin-4-amine

[0604]

[0605] TEA (0.1 mL, 0.69 mmol) was added to a stirred solution of pyrrolidine (0.29 g, 0.42 mmol) in THF (1.5 mL, 10 V). Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.15 g, 0.34 mmol) in THF (1.5 mL, 10 V) was added dropwise to the above solution under N2 atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (2 x 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal-phase chromatography by elution with (50:50) ethyl acetate / hexane to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(pyrrolidine-1-ylsulfonyl)pyrido[3,4-d]pyrimidine-4-amine (0.025 g, 15.43%), as a pale yellow solid.

[0606] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.303 min, m / z = 466.3 [M+H]+.

[0607] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 6.522 min.

[0608] 1H-NMR: (400 MHz, DMSO-d6): δ 9.34 (d, J = 6.8 Hz, 1H), 9.05 (s, 1H),9.03 (s, 1H), 7.71 (t, J =7.2 Hz, 1H), 7.53 (t, J =5.6 Hz, 1H), 7.32 (t, J =7.6Hz, 1H), 7.25 (s, 1H), 5.80-5.77 (m, 1H), 3.41-3.36 (m, 4H), 2.45 (s, 3H), 1.74-1.71 (m, 4H), 1.63 (d, J =7.2 Hz, 3H).

[0609] Example 5: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(morpholinosulfonyl) pyrido[3,4-d]pyrimidin-4-amine

[0610]

[0611] TEA (0.1 mL, 0.69 mmol) was added to a stirred solution of morpholine (0.36 g, 0.42 mmol) in THF (1.5 mL, 10 V). Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.15 g, 0.34 mmol) in THF (1.5 mL, 10 V) was added dropwise to the above solution under N2 atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (2 x 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal-phase chromatography and eluted with (32:68) ethyl acetate / hexane to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(morpholinosulfonyl)pyrido[3,4-d]pyrimidine-4-amine (0.012 g, 7.16%), a pale yellow solid.

[0612] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.176 min, m / z = 482.4 [M+H]+.

[0613] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 6.331 min.

[0614] 1H-NMR: (400 MHz, DMSO-d6): δ 9.35 (d, J = 6.8 Hz, 1H), 9.08 (s, 1H),9.05 (s, 1H), 7.71 (t, J =7.2 Hz, 1H), 7.53 (t, J =6.4 Hz, 1H), 7.32 (t, J =7.6Hz, 1H), 7.25 (s, 1H), 5.82-5.75 (m, 1H), 3.65 (t, J =4.4 Hz, 4H), 3.20 (m,4H), 2.45 (s, 3H), 1.63 (d, J =6.8 Hz, 3H).

[0615] Example 6: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-((4-methylpiperazine- 1-yl)sulfonyl)pyrido[3,4-d]pyrimidin-4-amine

[0616]

[0617] TEA (0.1 mL, 0.69 mmol) was added to a stirred solution of 1-methylpiperazine (0.041 g, 0.42 mmol) in THF (1.5 mL, 10 V). Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.15 g, 0.34 mmol) in THF (1.5 mL, 10 V) was added dropwise to the above solution under N2 atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (5% MeOH / DCM) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (2 x 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal-phase chromatography with (4:96) MeOH / DCM elution to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-((4-methylpiperazin-1-yl)sulfonyl)pyrido[3,4-d]pyrimidin-4-amine (0.011 g, 6.39%), as a pale yellow solid.

[0618] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.176 min, m / z = 482.4 [M+H]+.

[0619] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 6.331 min.

[0620] 1H-NMR: (400 MHz, DMSO-d6): δ 9.35 (d, J = 6.8 Hz, 1H), 9.07 (s, 1H), 9.03 (s, 1H), 7.71 (t, J =7.6 Hz, 1H), 7.53 (t, J =6.8 Hz, 1H), 7.32 (t, J=7.6Hz, 1H), 7.25 (s, 1H), 5.80-5.76 (m, 1H), 3.22 (m, 4H), 3.45 (s, 3H), 2.40-2.33 (m, 4H), 2.15 (s, 3H), 1.63 (d, J =7.2 Hz, 3H).

[0621] Example 7: (R)-1-(4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine pyrimidin-6-yl)sulfonyl)piperazin-1-yl) ethyl-1-one

[0622]

[0623] TEA (0.06 mL, 0.0004651 mol) was added to a stirred solution of 1-(piperazin-1-yl)ethyl-1-one (0.030 g, 0.0002325 mol) in THF (1 mL, 10 V). Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.1 g, 0.0002325 mol) in THF (1 mL, 10 V) was added dropwise to the above solution under N2 atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 16 hours. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (2 x 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain (R)-1-(4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)piperazin-1-yl)ethyl-1-one (0.029 g), which was a white solid.

[0624] LCMS Rt (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.067 min, m / z = 523.3 [M+H]+.

[0625] HPLC Rt (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 5.983 min.

[0626] 1H-NMR: (400 MHz, DMSO-d6): δ 9.34 (d, J = 6.8 Hz, 1H), 9.06 (s, 1H), 9.04 (s, 1H), 7.71 (t, J = 7.2 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.32 (t, J=7.6 Hz, 1H), 7.25 (s, 1H), 5.82-5.75 (m, 1H), 3.60 (brs, 4H), 3.23-3.22 (m,2H), 3.18-3.15 (m, 2H), 2.44 (s, 3H), 1.95 (s, 3H), 1.64 (d, J=7.2 Hz, 3H).

[0627] Example 8: (R)-N-cyclopentyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl Pyrido[3,4-d]pyrimidine-6-sulfonamide

[0628]

[0629] TEA (0.1 mL, 0.69 mmol) was added to a stirred solution of cyclopentylamine (0.035 g, 0.42 mmol) in THF (1.5 mL, 10 V). Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.15 g, 0.34 mmol) in THF (1.5 mL, 10 V) was added dropwise to the above solution under N2 atmosphere at 0°C. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (2 x 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by normal-phase chromatography by elution with (35:65) ethyl acetate / hexane to give (R)-N-cyclopentyl-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonamide (0.015 g, 9%), as a brown solid.

[0630] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.364 min, m / z = 480.3 [M+H]+.

[0631] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 6.769 min.

[0632] 1H-NMR: (400 MHz, DMSO-d6): δ 9.34 (d, J = 6.4 Hz, 1H), 9.06 (s, 1H), 9.03 (s, 1H), 7.94 (d, J =7.6 Hz, 1H), 7.71 (t, J =7.6 Hz, 1H), 7.53 (t, J =6.8Hz, 1H), 7.32 (t, J =8.0 Hz, 1H), 7.25 (s, 1H), 5.80-5.77 (m, 1H), 3.62-3.57(m, 1H), 2.45 (s, 3H), 1.63 (d, J =6.8 Hz, 3H), 1.60-1.55 (m, 4H), 1.35-1.29(m, 4H),.

[0633] Example 9: (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-N-phenylpyridine pyrimidine-6-sulfonamide

[0634]

[0635] TEA (0.06 mL, 0.00046 mol) was added to a stirred solution of aniline (0.022 g, 0.0002325 mol) in THF (1 mL, 10 V). Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.1 g, 0.000023 mmol) in THF (1 mL, 10 V) was added dropwise to the above solution at 0°C under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 16 hours. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (2 x 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with (40:60) ACN / water elution to give (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl-N-phenylpyrido[3,4-d]pyrimidine-6-sulfonamide (0.0106 g, 8%), as a gray solid.

[0636] LCMS Rt (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.379 min, m / z = 488.3 [M+H]+.

[0637] HPLC Rt (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 6.909 min.

[0638] 1H-NMR: (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 9.33 (d, J = 7.2 Hz,1H), 9.10 (s, 1H), 9.03 (s, 1H), 7.67 (t, J = 6.8 Hz, 1H), 7.52 (t, J = 6.8Hz, 1H), 7.37-7.29 (m, 1H), 7.23-7.15 (m, 5H), 7.01-6.98 (m, 1H), 5.78-5.74(m, 1H), 2.42 (s, 3H), 1.61 (t, J = 6.8 Hz, 3H).

[0639] Example 10: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(((R)-3-(dimethylamino) (1-yl)pyrrolidine-1-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0640]

[0641] TEA (0.15 g, 1.046 mmol, 3.0 equivalent) was added to a stirred solution of (R)-N,N-dimethylpyrrolidine-3-amine (0.15 g, 0.348 mmol, 2.0 equivalent) in THF (10 V) at 0°C under a nitrogen atmosphere. Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.079 g, 0.697 mmol, 1.0 equivalent) in THF (10 V) was added dropwise to the above solution. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (2 x 20 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography by elution with (80:20) acetonitrile / water to give N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(((R)-3-(dimethylamino)pyrrolidine-1-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (0.025 g, 14.12%), as a pale yellow solid.

[0642] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 1.932 min, m / z = 508.9 [M+H]+.

[0643] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 4.952 min.

[0644] 1H-NMR (400 MHz, DMSO-d6): δ 9.34 (d, J=7.20 Hz, 1H), 9.06 (s, 1H), 9.02 (s, 1H), 7.71 (t, J=7.20 Hz, 1H), 7.52 (t, J=6.80 Hz, 1H), 7.31 (t, J=7.60 Hz, 1H), 7.25 (s, 1H), 5.80-5.76 (m, 1H), 3.63-3.67 (m, 1H), 3.53-3.58(m, 1H), 3.07 (t, J=9.60 Hz, 2H), 2.40 (s, 3H), 2.15 (d, J=7.60 Hz, 2H), 2.04(s, 6H), 1.92-1.95 (m, 1H), 1.63 (d, J=6.00 Hz, 3H).

[0645] Example 11: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(((S)-3-(dimethylamino) (1-yl)pyrrolidine-1-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0646]

[0647] Add (S)-N,N-dimethylpyrrolidine-3-amine (0.026 g, 0.23 mmol) to a stirred solution in THF (10 V). Add TEA (0.069 g, 0.69 mmol) to the above mixture. Stir the resulting mixture at room temperature for 10 min. Add (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.1 g, 0.23 mmol) to the above mixture. Stir the resulting mixture at room temperature for 1 h. TLC (10% MeOH / DCM) showed complete consumption of SM. Dilute the resulting solution with water (30 mL) and ethyl acetate (60 mL). Dry the combined organic matter over Na2SO4, filter, and evaporate. The residue was purified by reversed-phase chromatography with (50%) ACN / water to give N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(((S)-3-(dimethylamino)pyrrolidine-1-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine (0.018 g, 20.61%) as a yellow solid.

[0648] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 1.935 min, m / z = 509 [M+H] +.

[0649] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 4.991 min.

[0650] 1H NMR (400 MHz, DMSO): δ 9.33 (d, J = 6.80 Hz, 1H), 9.06 (s, 1H), 9.03 (s, 1H), 7.71 (t, J = 7.60 Hz, 1H), 7.53 (t, J = 6.00 Hz, 1H), 7.38-7.11 (m, 2H), 5.77-5.80 (m, 1H), 3.51-3.63 (m, 1H), 3.11-3.18 (m, 1H), 2.45(s, 3H), 1.64-2.34 (m, 8H), 1.63 (d, J = 7.20 Hz, 3H), 1.25-1.34 (m, 3H).

[0651] Example 12: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((4-(2-methoxyethyl) Piperazine-1-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0652]

[0653] Add 1-(2-methoxyethyl)piperazine (0.033 g, 0.23 mmol) to a stirred solution in THF (10 V). Add TEA (0.069 g, 0.69 mmol) to the above mixture. Stir the resulting mixture at room temperature for 10 min. Add (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.1 g, 0.23 mmol) to the above mixture. Stir the resulting mixture at room temperature for 1 h. TLC (10% MeOH / DCM) showed complete consumption of SM. Dilute the resulting solution with water (30 mL) and EtOAC (60 mL). Dry the combined organic matter over Na2SO4, filter, and evaporate. Purify the residue by reversed-phase chromatography with (50%) ACN / water to obtain ( R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((4-(2-methoxyethyl)piperazin-1-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine (0.011 g, 12.60%), is a pale yellow solid.

[0654] LCMS t R(Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 1.974 min, m / z = 539 [M+H] +.

[0655] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 5.088 min.

[0656] 1H NMR (400 MHz, DMSO): δ 9.33 (d, J = 7.20 Hz, 1H), 9.07 (s, 1H), 9.03 (s, 1H), 7.71 (t, J = 7.60 Hz, 1H), 7.53 (t, J = 7.20 Hz, 1H), 7.31 (t,J = 7.60 Hz, 1H), 7.25 (s, 1H), 5.76-5.80 (m, 1H), 3.33-3.39 (m, 2H), 3.19-3.20 (m, 5H), 2.45-2.47 (m, 11H), 1.63 (d, J = 6.80 Hz, 3H).

[0657] Example 13: (R)-N-(1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl)sulfonyl)-3-methylazacyclobutane-3-yl)acetamide

[0658] Preparation 1: tert-butyl 3-acetamido-3-methylazacyclobutane-1-carboxylate

[0659]

[0660] 0.5 g (2.68 mmol) of tert-butyl 3-amino-3-methylazacyclobutane-1-carboxylate was dissolved in tetrahydrofuran (10 mL, 20 V). Pyridine (1.78 mL, 21.40 mmol) and acetyl chloride (0.78 mL, 10.70 mmol) were added to the above solution at room temperature. The suspension was stirred at room temperature for 2 hours. TLC (30:70 hexane / ethyl acetate) showed complete consumption of SM. The solution was neutralized by adding 1 N HCl solution, followed by extraction with ethyl acetate. The organic matter was dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by elution with 100% ethyl acetate to give 0.36 g (58%) of tert-butyl 3-acetamido-3-methylazacyclobutane-1-carboxylate, as a colorless viscous oil.

[0661] LCMS t R(Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 1.95 min, m / z = 285.2 [M+H]+.

[0662] Preparation 2: N-(3-methylazacyclobutane-3-yl)acetamide

[0663]

[0664] 0.5 g (1.57 mmol) of tert-butyl ethyl 3-acetamido-3-methylazacyclobutane-1-carboxylic acid was dissolved in dichloromethane (5.4 mL, 15 V). Trifluoroacetic acid (1.08 mL, 3 V) was added to the solution at 0°C. The suspension was stirred at room temperature for 2 hours. TLC (05:95 DCM / MeOH) showed complete consumption of SM. The resulting mixture was concentrated under vacuum to give N-(3-methylazacyclobutane-3-yl)acetamide (0.5 g, quantified) as a colorless viscous oil.

[0665] LCMS t R (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 0.26 min, m / z = 128.9 [M+H]+.

[0666] Example 13 : Preparation 3: (R)-N-(1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)- 2-Methylpyrido[3,4-d]pyrimidin-6-yl)sulfonyl)-3-methylazacyclobutane-3-yl)acetamide

[0667]

[0668] To a stirred solution of N-(3-methylazacyclobutane-3-yl)acetamide (0.066 g, 0.52 mmol) and DIPEA (0.17 mL, 1.04 mmol) in dichloromethane (1.5 mL, 10 V), add (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.15 g, 0.34 mmol) in dichloromethane (1.5 mL, 10 V) at room temperature. Stir the resulting mixture at room temperature for 2 hours. TLC (05:95 MeOH / DCM) showed complete consumption of SM. Dilute the resulting solution with water (50 mL) and extract with dichloromethane (50 mL). Dry the organic matter and concentrate under vacuum. The residue was purified by preparative-HPLC to obtain (R)-N-(1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)-3-methylazacyclobutane-3-yl)acetamide (0.018 g, 3%), a light green solid.

[0669] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.06 min, m / z = 522.9 [M+H] +.

[0670] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 6.53 min

[0671] 1H NMR (400 MHz, DMSO): δ 9.38 (d, J = 6.8 Hz, 1H), 9.11 (s, 1H), 9.06 (s, 1H), 8.11 (s, 1H), 7.72 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 6.4 Hz,1H), 7.12-7.39 (m, 2H), 5.76-5.83 (m, 1H), 4.03-4.10 (m, 2H), 3.81-3.83 (m,2H), 2.46 (s, 3H), 1.61-1.65 (m, 6H), 1.28 (d, J = 6.8 Hz, 3H).

[0672] Example 14: N-((R)-1-((4-((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- Methylpyrido[3,4-d]pyrimidin-6-yl)sulfonyl)pyrrolidine-3-yl)acetamide

[0673]

[0674] In 0 0 C(R)-N-(pyrrolidone-3-yl)acetamide (0.089 g, 0.0007 mol) was added to a stirred solution in dry THF with TEA. (0.141 g, 0.0014 mol) was followed by the addition of a solution of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.150 g, 0.00035 mol) in dry THF. The resulting reaction mixture was stirred at room temperature for 2 hours. TLC (1:9 MeOH / DCM) showed complete consumption of SM. The reaction mixture was diluted with DCM and water. The combined organic matter was dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by normal-phase chromatography with (04 / 96) MeOH / DCM elution to give N-((R)-1-((4-((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)pyrrolidine-3-yl)acetamide (0.017 g, 9%), as a pale yellow solid.

[0675] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.032 min, m / z = 522.9 [M+H] +

[0676] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 6.557 min

[0677] 1H NMR (400 MHz, DMSO-d6): δ 9.34 (d, J = 6.80 Hz, 1H), 9.04 (s, 1H), 9.02 (s, 1H), 7.93 (d, J = 6.00 Hz, 1H), 7.72 (t, J = 7.60 Hz, 1H), 7.53 (t, J = 6.40 Hz, 1H), 7.38-7.11 (m, 2H), 5.77-5.80 (t, J= 7.20 Hz, 1H), 4.05-4.09 (m, 1H), 3.43-3.59 (m, 4H), 3.18-3.25 (m, 1H), 2.45 (s, 3H), 1.93-1.98(m, 1H), 1.69 (s, 3H), 1.64 (d, J = 6.80 Hz, 3H).

[0678] Example 15: (R)-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine [3,4-d]pyrimidin-6-yl)sulfonyl)thiomorpholine 1,1-dioxide

[0679]

[0680] Add thiomorpholine 1,1-dioxide (0.094 g, 0.0006976 mol) to a stirred solution in THF (10 V). Add TEA (0.2 mL, 0.001398 mol) to the above mixture. Stir the resulting mixture at room temperature for 10 minutes. Add (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.2 g, 0.0004651 mol) to the above mixture. Stir the resulting mixture at room temperature for 1 hour. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. Dilute the resulting solution with water (30 mL) and EtOAC (60 mL). Dry the combined organic matter over Na2SO4, filter, and evaporate. The residue was purified by reversed-phase chromatography by elution with (50%) ACN / water to give (R)-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)thiomorpholine 1,1-dioxide (0.017 g) as a white solid.

[0681] LCMS Rt (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.176 min, m / z = 529.9 [M+H]+.

[0682] HPLC Rt (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 7.655 min.

[0683] 1H-NMR: (400 MHz, DMSO-d6: δ 9.33 (d, J = 7.20 Hz, 1H), 9.09 (s, 1H), 9.08 (s, 1H), 7.71 (t, J = 7.20 Hz, 1H), 7.53 (t, J = 6.80 Hz, 1H), 7.39-7.11(m, 2H), 5.82-5.75 (m, 1H), 3.76 (br s, 4H), 3.27 (br s, 4H), 2.45 (s, 3H), 1.63 (d, J = 6.80 Hz, 3H).

[0684] Example 16: (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((4,4-difluoropiperidine-1- (Sulfo)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0685]

[0686] Add 4,4-difluoropiperidine (0.056 g, 0.464 mmol) to a stirred solution in THF (1.0 mL). Add TEA (0.07 g, 0.696 mmol) and (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.1 g, 0.232 mmol) to this solution at room temperature. Stir the resulting reaction mixture at room temperature for 1 hour. TLC (40% ethyl acetate:hexane) showed that SM was consumed. Pour the reaction mixture into water (50 mL) and extract with ethyl acetate (3 x 50 mL). Concentrate the combined organic layers under reduced pressure. Purify the crude product by reversed-phase chromatography (72% ACN in water). (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((4,4-difluoropiperidin-1-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine (0.011 g, 9.19%) was obtained as a pale yellow solid.

[0687] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.408 min, m / z = 515.9 [M+H] +。

[0688] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 8.83 min

[0689] 400 MHz, DMSO-d6: δ 9.34 (d, J =6.8Hz, 1H), 9.07 (s, 2H), 7.71 (t, J =7.2Hz, 1H), 7.52 (t, J =7.2Hz, 1H), 7.31 (t, J =7.6Hz, 1H), 7.24 (s, 1H), 5.79-5.76 (m, 1H), 3.42-3.39 (m, 4H), 2.45 (s, 3H), 2.07-2.02 (m, 4H), 1.63 (d, J =6.8Hz, 3H).

[0690] Example 17: (R)-1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine [3,4-d]pyrimidin-6-yl)sulfonyl)-4-methylpiperidin-4-ol

[0691]

[0692] Add 0.026 g, 0.23 mmol of 4-methylpiperidin-4-ol (THF) to a stirred solution in THF (10 V). Add 0.069 g, 0.69 mmol of TEA to the above mixture. Stir the resulting mixture at room temperature for 10 min. Add (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.1 g, 0.23 mmol) to the above mixture. Stir the resulting mixture at room temperature for 1 h. TLC (10% MeOH / DCM) showed complete consumption of SM. Dilute the resulting solution with water (30 mL) and EtOAc (60 mL). Dry the combined organic matter over Na2SO4, filter, and evaporate. The residue was purified by reversed-phase chromatography by elution with (50%) ACN / water to give (R)-1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)-4-methylpiperidin-4-ol (0.015 g, 12.68%), as a brown solid.

[0693] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.121 min, m / z = 509.9 [M+H] +。

[0694] HPLC t R(Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 6.74 min.

[0695] 1H NMR (400 MHz, DMSO): δ 9.32 (d, J = 6.80 Hz, 1H), 9.08 (s, 1H), 9.02 (s, 1H), 7.71 (t, J = 7.20 Hz, 1H), 7.53 (t, J = 7.60 Hz, 1H), 7.32 (t,J = 7.60 Hz, 1H), 7.25 (s, 1H), 5.76-5.80 (m, 1H), 4.29 (s, 1H), 3.43-3.49(m, 2H), 2.96-3.18 (m, 2H), 2.47 (s, 3H), 1.64 (d, J = 6.80 Hz, 3H), 1.49-1.50 (m, 4H), 1.24 (s, 3H).

[0696] Example 18: 6-((6-oxa-3-azabicyclo[3.1.1]hept-3-yl)sulfonyl)-N-((R)-1-(3- (difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0697]

[0698] In 0 0 C-6-oxa-3-azabicyclo[3.1.1]heptane hydrochloride (0.047 g, 0.348 mmol) was dissolved in a stirred solution of dry THF. 0 C added TEA to the solution. (0.105 g, 1.04 mmol) and (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.150 g, 0.348 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. TLC (1:9 MeOH / DCM) showed that SM was consumed. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative-HPLC. 6-((6-oxa-3-azabicyclo[3.1.1]hept-3-yl)sulfonyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (0.014 g, 8.15%) was obtained as a creamy white solid.

[0699] LCMS t R(Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.147 min, m / z = 493.85 [M+H] +

[0700] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 6.609 min

[0701] 1H NMR (400 MHz, DMSO-d6): δ 9.78 (S, 1H), 9.11 (d, J = 3.2 Hz, 2H), 7.73 (t, J =8.0 Hz, 1H), 7.54 (t, J =6.8 Hz, 1H), 7.39-7.11 (m, 2H), 5.84-5.80 (m, 1H), 4.55 (d, J =6.4 Hz, 2H), 3.68-3.58 (m, 4H), 3.02-3.00 (m, 1H), 2.45 (s, 3H), 1.77 (d, J =9.2 Hz, 1H), 1.65 (d, J =7.2 Hz, 3H).

[0702] Example 19: (R)-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine [3,4-d]pyrimidin-6-yl)sulfonyl)piperazin-2-one

[0703]

[0704] In 0 0 C-piperazin-2-one (0.071 g, 0.0007 mol) was added to a stirred solution in dry THF with TEA. (0.141 g, 0.0014 mol) was added, followed by the addition of a solution of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-sulfonyl chloride (0.150 g, 0.00035 mol) in dry THF. The resulting reaction mixture was stirred at room temperature for 2 hours. TLC (1:9 MeOH / DCM) showed complete consumption of SM. The reaction mixture was diluted with DCM and water. The combined organic matter was dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by preparative-HPLC to give (R)-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)sulfonyl)piperazin-2-one (0.015 g, 9%) as a creamy white solid.

[0705] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.008 min, m / z = 494.8 [M+H] +

[0706] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 6.659 min

[0707] 1H NMR (400 MHz, DMSO-d6): δ 9.35 (d, J = 6.80 Hz, 1H), 9.07 (s, 1H), 9.04 (s, 1H), 8.07 (s, 1H), 7.71 (t, J = 7.60 Hz, 1H), 7.53 (t, J = 7.20 Hz,1H), 7.12-7.25 (m, 2H), 5.76-5.80 (m, 1H), 3.81 (d, J = 2.00 Hz, 2H), 3.46-3.48 (m, 2H), 3.15-3.17 (m, 2H), 2.45 (s, 3H), 1.64 (d, J = 6.80 Hz, 3H).

[0708] Example 20: 6-((2-oxa-5-azabicyclo[2.2.1]hept-5-yl)sulfonyl)-N-((R)-1-(3-(di) (Fluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0709]

[0710] In 0 0 C-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride (0.047 g, 0.348 mmol) was dissolved in a stirred solution of dry THF. 0 C added TEA to the solution. (0.105 g, 1.04 mmol) and (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.150 g, 0.348 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours. TLC (1:9 MeOH / DCM) showed that SM was consumed. The reaction mixture was poured into water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic layers were concentrated under reduced pressure. The crude product was purified by preparative-HPLC. 6-((2-oxa-5-azabicyclo[2.2.1]hept-5-yl)sulfonyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (0.021 g, 12.45%) was obtained as a creamy white solid.

[0711] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.137 min, m / z = 493.80 [M+H] +

[0712] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 7.449 min

[0713] 1H NMR (400 MHz, MeOD): δ 9.03 (s, 1H), 8.96 (s, 1H), 7.64 (t, J =8.0Hz, 1H), 7.50 (t, J = 6.4Hz, 1H), 7.26 (t, J =8.0Hz, 1H), 7.16-6.89 (m,2H), 5.89-5.83 (m, 1H), 4.66 (s, 1H), 4.56 (s, 1H), 3.90-3.88 (m, 1H), 3.74(d, J=7.6 Hz, 1H), 3.48-3.47 (m, 2H), 2.52 (s, 3H), 1.80-1.77 (m, 1H), 1.71(d, J =7.2Hz, 3H), 1.53 (d, J =10.4Hz, 1H).

[0714] Example 21: (R)-1-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl)sulfonyl)-2,6-diazaspiro[3.3]hept-2-yl)ethyl-1-one

[0715]

[0716] Add 2,2,2-trifluoro-113-ethyl-1-one (1:1) (0.162 g, 0.58 mmol) in THF (2 mL) to a stirred solution of 1-(2,6-diazaspiro[3.3]hepta-2-yl)ethyl-1-one. Add TEA (0.117 g, 1.16 mmol) and (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.250 g, 0.58 mmol) to this solution at room temperature. Stir the resulting reaction mixture at room temperature for 1 hour. TLC (10% MeOH: DCM) showed that SM was consumed. Pour the reaction mixture into water (50 mL) and extract with ethyl acetate (3 x 50 mL). Concentrate the combined organic layers under reduced pressure. The crude product was purified by reversed-phase chromatography (50% ACN in water). The resulting product was (R)-1-(6-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino (0.019 g, 6.13%), a creamy-white solid.

[0717] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.052 min, m / z = 534.91 [M+H] +。

[0718] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 6.40 min

[0719] 400 MHz, DMSO-d6: δ 9.38 (d, J =6.8Hz, 1H), 9.11 (s, 1H),9.06 (s, 1H),7.72 (t, J=7.2Hz, 1H), 7.53 (t, J =7.2Hz, 1H), 7.39-7.11 (m, 2H), 5.81-5.77(m, 1H), 4.176 (m, 4H), 4.09 (s, 2H), 2.80 (s, 2H), 2.46 (s, 3H), 1.65-1.62(m, 6H).

[0720] Example 22: (R)-1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine [3,4-d]pyrimidin-6-yl)sulfonyl)piperidin-4-ol

[0721]

[0722] TEA (0.140 g, 1.395 mmol) was added to a stirred solution of piperidine-4-ol (0.093 g, 0.930 mmol) in THF (10 V). (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.2 g, 0.465 mmol) in THF (10 V) was added dropwise to the above solution at 0°C under a nitrogen atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (3 x 10 mL). The combined organic compounds were dried over Na2SO4, filtered, and concentrated under reduced vacuum. The residue was purified by preparative HPLC to obtain (R)-1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)piperidin-4-ol (0.02 g, 8.69%), as a white solid.

[0723] LCMS t R (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.058 min, m / z = 495.8 [M+H]+.

[0724] HPLC t R (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 6.383 min.

[0725] 1H-NMR: (400 MHz, DMSO-d6): δ 9.35 (d, J = 6.80 Hz, 1H), 9.07 (s,1H), 9.03 (s, 1H), 7.71 (t, J = 7.60 Hz, 1H), 7.54 (t, J = 7.20 Hz, 1H), 7.33(t, J = 8.00 Hz, 1H), 7.26 (s, 1H), 5.80-5.75 (m, 1H), 4.74 (d, J = 4.00 Hz,1H), 3.50-3.58 (m, 1H), 3.42-3.49 (m, 2H), 3.00-3.02 (m, 2H), 2.46 (s, 3H), 1.74-1.77 (m, 2H), 1.64 (d, J = 7.20 Hz, 3H), 1.38-1.48 (m, 2H).

[0726] Example 23: (R)-N-(1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl Pyrido[3,4-d]pyrimidin-6-yl)sulfonyl)azacyclobutane-3-yl)acetamide

[0727]

[0728] Add N-(azacyclobutane-3-yl)acetamide hydrochloride (0.140 g, 0.93 mmol) to a stirred solution in THF (2 mL). Add TEA (0.215 g, 1.86 mmol) and (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.2 g, 0.46 mmol) to this solution at room temperature. Stir the resulting reaction mixture at room temperature for 1 hour. TLC (50% ethyl acetate: hexane) showed that SM was consumed. Pour the reaction mixture into water (50 mL) and extract with ethyl acetate (3 x 50 mL). Concentrate the combined organic layers under reduced pressure. Purify the crude product by reversed-phase chromatography (45% ACN in water). (R)-N-(1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)azacyclobutane-3-yl)acetamide (0.019 g, 8.04%) was obtained as a creamy white solid.

[0729] LCMS tR (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.038 min, m / z = 508.8 [M+H] +。

[0730] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 6.408 min.

[0731] 1H NMR (400 MHz, DMSO-d6): δ 9.38 (d, J =6.8Hz, 1H), 9.13 (s, 1H),9.06(s, 1H), 8.31 (d, J =6.8Hz, 1H), 7.71 (t, J =7.2Hz, 1H), 7.53 (t, J =7.2Hz, 1H),7.39-7.11 (m, 2H), 5.82-5.76 (m, 1H), 4.37-4.32 (m, 1H), 4.18-4.13 (m, 2H),3.81-3.77 (m, 2H), 2.47 (s, 3H), 1.72 (s, 3H), 1.64-1.62 (d, J =6.8Hz, 3H)

[0732] T244

[0733] Synthesis process:

[0734]

[0735] Example 24: 1-(5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine pyrimidin-6-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl-1-one

[0736] Preparation of 1: 5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridinium [3,4-d]pyrimidin-6-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0737]

[0738] TEA (0.2 mL, 1.39 mmol) was added to a stirred solution of tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (0.16 g, 0.83 mmol) in THF (1.5 mL, 5 V). Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.3 g, 0.69 mmol) in THF (1.5 mL, 5 V) was added dropwise to the above solution at 0°C under a N2 atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (20 mL) and ethyl acetate (3 x 30 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by normal-phase chromatography and eluted with (31:69) ethyl acetate / hexane to give 5-((4-((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.25 g, 15.43%), as a yellow solid.

[0739] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.303 min, m / z = 466.3 [M+H]+.

[0740] Preparation 2: 6-((2,5-diazabicyclo[2.2.1]hept-2-yl)sulfonyl)-N-((R)-1-(3-(difluoromethyl) (2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0741]

[0742] A solution of 0.25 g (0.42 mmol) of 5-((4-((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in 4 M dioxane in HCl (4.2 mL, 10 V) was stirred at room temperature for 2 h. TLC (100% ethyl acetate) showed complete consumption of SM. The resulting solution was diluted with saturated NaHCO3 solution (15 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography and eluted with (48:52)ACN / water to give 6-((2,5-diazabicyclo[2.2.1]hept-2-yl)sulfonyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyridano[3,4-d]pyrimidin-4-amine (0.1 g, 48.13%) as a yellow solid.

[0743] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 1.900 min, m / z = 492.8 [M+H]+.

[0744] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 4.022 min.

[0745] 1H-NMR (400 MHz, DMSO-d6): δ 9.33 (d, J = 7.2 Hz, 1H), 9.07(s, 1H),9.02 (s, 1H), 7.71 (t, J =7.6 Hz, 1H), 7.53 (t, J =6.8 Hz, 1H), 7.32 (t, J =8.0Hz, 1H), 7.25 (s, 1H), 5.80-5.77 (m, 1H), 4.39-4.41 (m, 1H), 3.54 (s, 1H), 3.26 (s, 2H), 2.88-2.79 (m, 2H), 2.45 (s, 3H), 1.63 (d, J =6.8 Hz, 3H), 1.44(d, J =9.6 Hz, 1H), 1.15 (d, J=9.6 Hz, 1H), 0.88-0.85 (m, 1H).

[0746] Preparation Example 24: 1-(5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methyl pyrido[3,4-d]pyrimidin-6-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl-1-one

[0747]

[0748] A solution of 6-((2,5-diazabicyclo[2.2.1]hept-2-yl)sulfonyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (0.08 g, 0.16 mmol) in DCM (2 mL) was added to TEA (0.033 g, 0.05 mL, 0.324 mmol) and stirred for 10 minutes. Then, acetic anhydride (0.02 g, 0.19 mmol) in DCM (0.5 mL) was added dropwise to the above solution at 0°C under a N2 atmosphere. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (10% MeOH / DCM) showed complete consumption of SM. The resulting solution was diluted with water (5 mL) and DCM (3 x 30 mL). The combined organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography with (40:60) ACN / water elution to give 1-(5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl-1-one (0.043 g, 49.52%), as a white solid.

[0749] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.038 min, m / z = 534.9 [M+H]+.

[0750] HPLC tR (Waters Alliance e2695, with 2998 detector, acidic, 17.0 min): 6.846 min.

[0751] 1H-NMR (400 MHz, DMSO-d6): δ 9.35 (brs, 1H), 9.08-9.03(m, 2 H), 7.72(t, J =7.6 Hz, 1H), 7.54 (t, J=6.8 Hz, 1H), 7.35-7.31 (m, 1H), 7.26 (s, 1H), 5.81-5.78 (m, 1H), 4.64 (d, J =7.6 Hz, 1H), 4.56 (d, J =7.6 Hz, 1H), 3.48-3.40(m, 2H), 3.21 (d, J =12.4 Hz, 1H), 2.46 (s, 3H), 1.99 (d, J =2.0 Hz, 2H), 1.79(d, J =5.6 Hz, 2H), 1.75-1.71 (m, 1H), 1.64 (d, J =6.8 Hz, 3H), 1.55-1.40 (m,1H).

[0752] Example 25: (R)-2-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine [3,4-d]pyrimidin-6-yl)sulfonyl)-2,6-diazaspiro[3,4]oct-7-one

[0753] Preparation 1: (R)-2-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridin [3,4-d]pyrimidin-6-yl)sulfonyl)-2,6-diazaspiro[3,4]oct-7-one

[0754]

[0755] TEA (0.105 g, 1.046 mmol, 3.0 equivalent) was added to a stirred solution of 2,6-diazaspiro[3,4]oct-7-one hydrochloride (0.15 g, 0.348 mmol, 2.0 equivalent) in THF (10 V) at 0°C under N2 atmosphere. Then, (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.113 g, 0.697 mmol, 1.0 equivalent) in THF (10 V) was added dropwise to the above solution. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% ethyl acetate / hexane) showed complete consumption of SM. The resulting solution was diluted with water (10 mL) and ethyl acetate (3 x 10 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced vacuum. The residue was purified by reversed-phase chromatography by elution with (80:20) acetonitrile / water to give (R)-2-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridano[3,4-d]pyrimidin-6-yl)sulfonyl)-2,6-diazaspiro[3,4]oct-7-one (0.015 g, 8.28%), as a pale yellow solid.

[0756] LCMS tR (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.019 min, m / z = 520.8 [M+H]+.

[0757] HPLC tR (Waters Alliance e2695 with 2998 detector, acidic, 17.0 min): 5.76 min.

[0758] 1H-NMR (400 MHz, DMSO-d6): δ 9.38 (d, J = 7.20 Hz, 1H), 9.14 (s, 1H), 9.06 (s, 1H), 7.72 (t, J = 7.20 Hz, 1H), 7.51-7.57 (m, 2H), 7.25-7.39 (m,2H), 5.75-5.82 (m, 1H), 3.98-4.05 (m, 4H), 3.24 (s, 2H), 2.50 (s, 3H), 2.27(s, 2H), 1.63 (d, J = 7.20 Hz, 3H).

[0759] Example 26: (R)-6-((2-oxa-6-azaspiro[3.3]hept-6-yl)sulfonyl)-N-(1-(3-(difluoromethyl) (2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0760] Preparation 1: (R)-6-((2-oxa-6-azaspiro[3.3]hept-6-yl)sulfonyl)-N-(1-(3-(difluoromethyl) (2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0761]

[0762] Add 0.022 g, 0.23 mmol of 2-oxa-6-azaspiro[3.3]heptane (THF) to a stirred solution in 10 V THF. Add 0.069 g, 0.69 mmol of TEA to the above mixture. Stir the resulting mixture at room temperature for 10 min. Add (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.1 g, 0.23 mmol) to the above mixture. Stir the resulting mixture at room temperature for 1 h. TLC (10% MeOH / DCM) showed complete consumption of SM. Dilute the resulting solution with water (30 mL) and ethyl acetate (60 mL). Dry the combined organic matter over Na2SO4, filter, and evaporate. The residue was purified by reversed-phase chromatography by elution with (50%) ACN / water to give (R)-6-((2-oxa-6-azaspiro[3.3]hept-6-yl)sulfonyl)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (0.004 g, 3.49%) as a yellow solid.

[0763] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.134 min, m / z = 494 [M+H] +。

[0764] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 7.43 min.

[0765] 1H NMR (400 MHz, DMSO) δ: 9.37(d, J = 7.2 Hz, 1H), 9.08 (s, 1H), 9.05(s, 1H), 7.72 (t, J =7.2 Hz, 1H), 7.54 (t, J =7.2 Hz, 1H), 7.40-7.26 (m, 2H), 5.80 (t, J =7.2 Hz, 1H), 4.52 (s, 4H), 4.24-4.18 (m, 4H), 2.47 (s, 3H), 1.64 (d, J = 7.2 Hz, 3H).

[0766] Example 27: 1-(5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine Aceto[3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)ethyl-1-one

[0767] Preparation of 1: 5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridinium [3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-tert-butyl carboxylate

[0768]

[0769] A solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-carboxylate (0.22 g, 1.04 mmol) in dichloromethane (3 mL, 10 V) was added. DIPEA (0.35 mL, 2.09 mmol) and (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.3 g, 0.697 mmol) were added to the above solution, and the suspension was stirred at room temperature for 16 hours. TLC (70:30 hexane / ethyl acetate) showed complete consumption of SM. The reaction mixture was concentrated to give a crude heavy oil. The crude product was purified by elution with 70-80% ethyl acetate in hexane to give tert-butyl 5-((4-((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid (0.2 g, 47%), which is a viscous light green solid.

[0770] LCMS t R (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 2.46 min, m / z = 607.1 [M+H]+.

[0771] Preparation 2: N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((hexahydropyrrolo[3,4-c]pyridine) pyrido-2(1H)-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0772]

[0773] A solution of 0.2 g (0.33 mmol) of tert-butyl 5-((4-((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid in dichloromethane (2 mL, 10 V) was added. Trifluoroacetic acid (0.6 mL, 3 V) was added to the solution at 0°C. The suspension was stirred at room temperature for 2 hours. TLC (10:90 DCM / MeOH) showed complete consumption of SM. The resulting mixture was concentrated under vacuum to obtain N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine (0.18 g, quantitative), which was a creamy white solid.​

[0774] LCMS t R (Waters Acquity UPLC with QDA mass spectrometer detector, acidic, 4.0 min): 1.93 min, m / z = 506.9 [M+H]+.

[0775] Preparation 3 Example 27: 1-(5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2- Methylpyrido[3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)ethyl-1-one

[0776]

[0777] Triethylamine (0.10 mL, 0.768 mmol) was added to a stirred solution of N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-((hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine (0.13 g, 0.256 mmol) in dichloromethane (2.6 mL, 20 V). Acetic anhydride (0.12 mL, 1.28 mmol) was added dropwise to the above solution at room temperature. The resulting mixture was stirred at room temperature for 1 hour. TLC (05:95 MeOH / DCM) showed complete consumption of SM. The resulting solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL). The organic matter was dried and concentrated under vacuum. The residue was purified by preparative-HPLC to obtain 1-(5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)ethyl-1-one (0.0054 g, 4%), as a white solid.

[0778] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.02 min, m / z = 549.0 [M+H] +。

[0779] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 5.86 min

[0780] 1H NMR (400 MHz, DMSO): δ 9.37 (d, J =7.20 Hz, 1H), 9.06 (d, J = 1.60Hz, 2H), 7.72 (t, J=7.20 Hz, 1H), 7.53 (t, J =7.20 Hz, 1H), 7.13-7.40 (m, 2H),5.78-5.81 (m, 1H), 3.60-3.67 (m, 4H), 3.19-3.29 (m, 3H), 3.04-3.10 (m, 1H),2.89-2.93 (m, 1H), 2.78-2.83 (m, 1H), 2.46 (s, 3H), 1.87 (s, 3H), 1.64 (d, J =6.8 Hz, 3H).

[0781] Example 28: (R)-1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridine [3,4-d]pyrimidin-6-yl)sulfonyl)-3-methylazine-3-ol

[0782] Preparation 1: (R)-1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridin [3,4-d]pyrimidin-6-yl)sulfonyl)-3-methylazonyl-3-ol

[0783]

[0784] To a stirred solution of 3-methylazacyclobutane-3-ol hydrochloride (0.083 g, 0.123 mmol) in THF (2.0 ml), TEA (0.156 g, 1.34 mmol) and (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.145 g, 0.337 mmol) were added to the reaction mixture at room temperature. The resulting reaction mixture was stirred at room temperature for 1 hour. TLC (50% ethyl acetate: hexane) showed that SM was consumed. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reversed-phase chromatography (40% ACN in water). (R)-1-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)sulfonyl)-3-methylazacyclobutane-3-ol (0.012 g, 7.41%) was obtained as a solid, a pale yellow substance.

[0785] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.087 min, m / z = 481.8 [M+H] +。

[0786] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 7.13 min

[0787] 1H NMR (400 MHz, DMSO): δ 9.37 (d, J =7.2Hz, 1H), 9.11 (s, 1H), 9.04(s, 1H), 7.71 (t, J =7.6Hz, 1H), 7.52 (t, J =7.2Hz, 1H), 7.31 (t, J =7.6Hz, 1H),7.24 (s, 1H), 5.78-5.79 (m, 1H), 5.56 (s, 1H), 3.78 (s, 4H), 2.46 (s,3H),1.63 (d, J=6.8Hz, 3H), 1.24 (s, 3H).

[0788] Example 29: (R)-6-((2-oxa-7-azaspiro[3.5]non-7-yl)sulfonyl)-N-(1-(3-(difluoromethyl) (2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0789] Preparation 1: (R)-6-((2-oxa-7-azaspiro[3.5]non-7-yl)sulfonyl)-N-(1-(3-(difluoromethyl) (2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidin-4-amine

[0790]

[0791] In 0 0 Triethylamine (0.106 g, 0.00104 mol) was added to a stirred solution of 2-oxa-7-azaspiro[3.5]nonane (0.044 g, 0.00035 mol) in dry THF, followed by a solution of (R)-4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidine-6-sulfonyl chloride (0.150 g, 0.00035 mol) in dry THF. The resulting reaction mixture was stirred at room temperature for 2 hours. TLC (1:9 MeOH / DCM) showed complete consumption of SM. The reaction mixture was diluted with DCM and water. The combined organic matter was dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by reversed-phase chromatography with (46 / 54) ACN / water elution to give (R)-N-(1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-oxo-1-(1H-pyrazol-4-yl)-1,6-dihydropyridazine-3-carboxamide (0.047 g, 26%) as a creamy white solid.

[0792] LCMS t R (Waters Acquity UPLC, with QDA mass spectrometer detector, acidic, 4.0 min): 2.188 min, m / z = 521.9 [M+H]+

[0793] HPLC t R (Waters Alliance e2695, with 2998 detector, alkaline, 17.0 min): 6.811 min

[0794] 1H NMR (400 MHz, DMSO-d6): δ 9.33 (d, J = 6.80 Hz, 1H), 9.04 (s, 1H), 9.01 (s, 1H), 7.71 (t, J = 7.20 Hz, 1H), 7.53 (t, J = 6.80 Hz, 1H), 7.12-7.39(m, 2H), 5.76-5.80 (m, 1H), 4.22 (s, 4H), 3.13-3.15 (m, 4H), 2.44 (s, 3H),1.82-1.85 (m, 4H), 1.63 (d, J = 6.80 Hz, 3H).

[0795] Example 30 - 1-(5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethyl-1-one

[0796]

[0797] 1H nmr: δ 9.35 (brs, 1H), 9.08-9.03(m, 2H), 7.72 (t, J =7.6 Hz, 1H), 7.54 (t, J =6.8 Hz, 1H), 7.35-7.31 (m, 1H), 7.26 (s, 1H), 5.81-5.78(m, 1H), 4.64 (d, J =7.6 Hz, 1H), 4.56 (d, J =7.6 Hz, 1H), 3.48-3.40 (m, 2H), 3.21 (d, J =12.4 Hz, 1H), 2.46 (s, 3H), 1.99 (d, J =2.0 Hz, 2H), 1.79 (d,J =5.6 Hz, 2H),1.75-1.71 (m, 1H), 1.64 (d, J =6.8 Hz, 3H), 1.55-1.40 (m, 1H).

[0798] Example 31 - 1-(5-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrolo-2(1H)-yl)ethyl-1-one

[0799]

[0800] 1H nmr: δ 9.37 (d, J =7.20 Hz, 1H), 9.06 (d, J = 1.60 Hz, 2H), 7.72(t, J =7.20 Hz, 1H), 7.53 (t, J =7.20 Hz, 1H), 7.13-7.40 (m, 2H), 5.78-5.81 (m,1H), 3.60-3.67 (m, 4H), 3.19-3.29 (m, 3H), 3.04-3.10 (m, 1H), 2.89-2.93 (m,1H), 2.78-2.83 (m, 1H), 2.46 (s, 3H), 1.87 (s, 3H), 1.64 (d, J =6.8 Hz, 3H).

[0801] Example 32 - (R)-4-((4-((1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)sulfonyl)-N-methylpiperazine-1-carboxamide

[0802]

[0803] 1H nmr: δ 9.33 (d, J=6.8 Hz, 1H), 9.04-9.08 (m, 2H), 7.70-7.73 (m,1H), 7.51-7.55 (m, 1H), 7.12-7.39 (m, 2H), 6.50 (d, J=4.4 Hz, 1H), 5.75-5.81(m, 1H), 3.62 (s, 3H), 3.36-3.47 (m, 4H), 3.15-3.23 (m, 4H), 2.39 (s, 3H), 1.61 (d, J=7.2 Hz, 3H).

[0804] Example 33 - (S)-1-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)pyrrolidine-3-ol

[0805]

[0806] 1H nmr: δ 9.34 (d, J=6.8 Hz, 1H), 9.01-9.04 (m, 2H), 7.70-7.73 (m,1H), 7.51-7.55 (m, 1H), 7.12-7.39 (m, 2H), 5.75-5.82 (m, 1H), 4.88 (bs, 1H), 4.18 (bs, 1H), 3.51-3.55 (m, 2H), 3.42-3.49 (m, 2H), 2.44 (s, 3H), 1.73-1.82(m, 1H), 1.69-1.69 (m, 1H), 1.63 (d, J=7.2 Hz, 3H).

[0807] Example 34 - (R)-1-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)piperidin-3-ol

[0808]

[0809] 1H nmr: δ 9.34 (d, J=7.2 Hz, 1H), 9.02-9.07 (m, 2H), 7.71 (t, J=7.2Hz, 1H), 7.53 (t, J=6.8 Hz, 1H), 7.25-7.39 (m, 2H), 5.77-5.80 (m, 1H), 5.07(s, 1H), 4.98 (d, J=4.4 Hz, 1H), 3.62-3.66 (m, 1H), 3.47-3.54 (m, 2H), 2.68-2.78 (m, 1H), 2.45 (s, 3H), 1.71-1.78 (m, 2H), 1.64 (d, J=6.8 Hz, 3H), 1.43-1.46 (m, 1H), 1.15-1.20 (m, 1H).

[0810] Example 35 - (S)-1-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)piperidin-3-ol

[0811]

[0812] 1H nmr: δ 9.33 (d, J=6.8 Hz, 1H), 9.02-9.06 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.11-7.38 (m, 2H), 5.74-5.81 (m, 1H), 4.98(d, J=4.4 Hz, 1H), 3.63-3.65 (m, 1H), 3.47-3.51 (m, 2H), 2.67-2.74 (m, 1H),2.54-2.59 (m, 1H), 2.44 (s, 3H), 1.70-1.78 (m, 2H), 1.63 (d, J=7.2 Hz, 3H),1.46-1.47 (m, 1H), 1.10-1.21 (m, 1H)

[0813] Example 36 - N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(((3R,5R)-3,4,5-trimethylpiperazin-1-yl)sulfonyl)pyrido[3,4-d]pyrimidine-4-amine

[0814]

[0815] 1H nmr: δ 9.31 (d, J=6.8 Hz, 1H), 9.01-9.06 (m, 2H), 7.71 (t, J=7.6Hz, 1H), 7.52 (t, J=6.8 Hz, 1H), 7.11-7.38 (m, 2H), 5.74-5.81 0.87-0.99 (m, 6H))

[0816] Example 37 - N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-6-(((R)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)sulfonyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine

[0817]

[0818] 1H nmr: δ 9.33 (d, J=7.2 Hz, 1H), 9.04-9.07 (m, 2H), 7.71 (t, J=7.2Hz, 1H), 7.53 (t, J=6.8 Hz, 1H), 7.12-7.39 (m, 2H), 5.75-5.82 (m, 1H), 3.86(d, J=10.4 Hz, 1H), 3.69 (d, J=11.6 Hz, 1H), 2.93-3.00 (m, 2H), 2.75-2.91 (m,1H), 2.53-2.56 (m, 1H), 2.45 (s, 3H), 2.12-2.15 (m, 1H), 2.07-2.10 (m, 1H), 1.91-2.05 (m, 1H), 1.74-1.81 (m, 1H), 1.63-1.65 (m, 5H), 1.22-1.30 (m, 1H).

[0819] Example 38 - N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methyl-6-(((3S, 5R)-3, 4, 5-trimethylpiperazin-1-yl)sulfonyl)pyrido[3,4-d]pyrimidine-4-amine

[0820]

[0821] 1H nmr: δ 8.93-9.03 (m, 2H), 7.63-7.67 (m, 1H), 7.50-7.53 (m, 1H), 7.27 (t, J=7.6Hz, 1H), 6.90-7.17 (m, 1H), 5.86-5.88 (m, 1H), 3.75 (d, J=11.6Hz, 2H), 2.54-2.61 (m, 5H), 2.37 (bs, 2H), 2.29 (s, 3H), 1.73 (d, J=7.2 Hz,3H), 1.12 (d, J = 6.4 Hz, 6H).

[0822] Example 39 - 1-(8-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)ethyl-1-one

[0823]

[0824] 1H nmr: δ 9.32 (d, J=7.2Hz, 1H), 9.04-9.08 (m, 2H), 7.70 (t, J=7.2Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.11-7.38 (m, 2H), 5.73-5.79 (m, 1H), 4.27-4.30 (m, 2H), 4.20 (d, J=12.8 Hz, 1H), 3.71 (d, J=12.0 Hz, 1H), 3.29 (d, J=13.2Hz, 1H), 2.73-2.77 (m, 1H), 2.44 (s, 3H), 1.98 (s, 3H), 1.64 (d, J=6.8Hz, 3H), 1.54-1.60 (m, 1H), 1.33-1.41 (m, 3H)

[0825] Example 40 - 1-((R)-4-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyrido[3,4-d]pyrimidin-6-yl)sulfonyl)-2-methylpiperazin-1-yl)ethyl-1-one

[0826]

[0827] 1H nmr: δ 9.33 (d, J=6.8 Hz, 1H), 9.04 (d, J=6.8 Hz, 2H), 7.71 (t, J=7.6 Hz, 1H), 7.53 (t, J=6.8 Hz, 1H), 7.11-7.38 (m, 2H), 5.76-5.81 (m, 1H),4.66 (bs, 1H), 4.30 (d, J=12.8 Hz, 1H), 4.18 (bs, 1H), 3.72 (bs, 1H), 3.52(d, J=12.4 Hz, 1H), 2.84-2.89 (m, 1H), 2.74-2.80 (m, 1H), 2.45 (s, 3H), 1.96(d, J=14.0 Hz, 3H), 1.63 (d, J=6.8 Hz, 3H), 1.10-1.25 (m, 3H).

[0828] Example 41 - 1-((S)-4-((4-((((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)-2-methylpiperazin-1-yl)ethyl-1-one

[0829]

[0830] 1H nmr: δ 9.15 (d, J=6.40 Hz, 1H), 9.02 (d, J=10.0 Hz, 2H), 7.73 (t,J=7.6 Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 7.06-7.33 (m, 2H), 5.80-5.84 (m, 1H),4.41 (bs, 1H), 3.99 (bs, 1H), 3.75 (d, J=10.4 Hz, 1H), 3.57 (d, J=12.0 Hz,1H), 3.20-3.23 (m, 1H), 2.89-2.92 (m, 1H), 2.74 (bs, 1H), 2.47 (s, 3H), 1.98 (s, 3H), 1.67 (d, J=7.2 Hz, 3H), 1.19 (d, J=5.6 Hz, 3H).

[0831] Example 42 - (S)-2-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0832]

[0833] 1H nmr: δ 9.34 (d, J=7.2 Hz, 1H), 9.05 (d, J=3.6 Hz, 2H), 7.71 (t, J=7.20 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.12-7.39 (m, 2H), 5.75-5.82 (m, 1H),3.87-3.90 (m, 2H), 3.78-3.81 (m, 1H), 3.58-3.65 (m, 1H), 2.80-2.85 (m, 1H),2.61-2.68 (m, 2H), 2.45 (s, 3H), 2.16-2.29 (m, 2H), 2.08-2.14 (m, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.48-1.57 (m, 1H).

[0834] Example 43 - (R)-2-((4-(((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)amino)-2-methylpyridino[3,4-d]pyrimidin-6-yl)sulfonyl)hexahydropyrrolo[1,2-a]pyrazin-6(2H)-one

[0835]

[0836] 1H nmr: δ 9.34 (d, J=7.20 Hz, 1H), 9.06 (d, J=3.6 Hz, 2H), 7.71 (t, J=7.2 Hz, 1H), 7.53 (t, J=7.60 Hz, 1H), 7.25-7.42 (m, 2H), 5.79 (t, J=7.2 Hz,1H), 3.87-3.90 (m, 2H), 3.77-3.79 (m, 1H), 3.59-3.61 (m, 1H), 2.82-2.87 (m,1H), 2.45 (s, 3H), 2.18-2.26 (m, 2H), 2.09-2.14 (m, 1H), 1.64 (d, J=6.8 Hz,3H), 1.48-1.57 (m, 2H).

[0837] Identification of SOS1 inhibitors:

[0838] Following the manufacturer's instructions, compounds were screened using the Cis Bio HTRF KRAS WT / SOS1 PPI kit, with modifications as follows: All reagents were equilibrated to room temperature and diluted to working stock solutions in binding domain detection buffer (BDD buffer). Stock solutions were prepared by adding 1 part Tag1-KRAS WT / GTP to 1 part Tag2-SOS1 and 1 part BDD. Separately, 1 part anti-Tag1 XL665 antibody premix was added to the anti-Tag2 Tb cavitation compound antibody premix.

[0839] BI-3406 (Selleck Chemicals) was used as a standard and dissolved in DMSO to a final concentration of 10 mM. The test compounds were also dissolved in DMSO to a final concentration of 10 mM. Then, using a Labcyte Echo 650 instrument, the test compounds were serially dispensed in 1 / 2-log, 10-point dilutions (starting at 10 μM) to distribute 200 nL of compound / well into a 384-well microplate (Greiner 784075). Using an E1-ClipTip™ electronically adjustable multichannel equalizer pipette, 6 μL of Tag1-KRAS WT / GTP premix, 4 μL of Tag2-SOS1 premix, and 10 μL of anti-Tag1 XL665 and anti-Tag2 Tb cavitation compound antibodies were added to each well. After the final addition, the plate was covered and placed in a benchtop incubator set to 22°C. The reactions were incubated at room temperature for 60 minutes before reading using a Phrastar FSX plate reader.

[0840] When tested in this experiment, all compounds of the present invention exhibited an IC50 of less than 500 nM. 50 .

[0841] Compound of Example 18: IC50 of 6-((6-oxa-3-azabicyclo[3.1.1]hept-3-yl)sulfonyl)-N-((R)-1-(3-(difluoromethyl)-2-fluorophenyl)ethyl)-2-methylpyrido[3,4-d]pyrimidine-4-amine 50 <100nM.

Claims

1. Compounds of formula (I) Or a pharmaceutically acceptable salt or solvate thereof, wherein: X is N or CR 25 , R 1 Selected from 4-7 membered saturated heterocycles containing N, optionally containing additional O, N, or S atoms, or an S(O)2 group, wherein the heterocycle optionally contains: (i) ether bridge or (ii) Connecting another 4-7 member N-containing saturated heterocycle to form a spirobicyclic group; or (iii) Connected to another 3-6 member N-containing saturated heterocycle, such that each ring shares two atoms, wherein the saturated heterocycle optionally contains a C(O) group; The monocyclic or bicyclic heterocycle is optionally substituted by 1-3 substituents, each of which is independently selected from NC(O)C. 1-6 Alkyl, H, N(C) 1-6 Alkyl)(C 1-6 Alkyl), C 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, OH and OC 1-6 Alkyl, HC(O)C 1-6 Alkyl, halogen, and Ph R 2 Selected from and R 3 It is H or NH2. R 4 It consists of CF3, CF2CH2OH, and CN. R 5 It's halogen. R 6 It's H. R 7 It's H. R 8 It is Ph, which is substituted at the ortho position with CH2NHCH3. R 25 Selected from H, OCH3, F and CN.

2. The compound according to claim 1, wherein R 2 yes R 3 It is H or NH2. R 4 It consists of CF3, CF2CH2OH, and CN. R 5 It is F.

3. The compound according to claim 1, wherein R 2 yes R 6 It's H. R 7 It's H. R 8 It is Ph, which is substituted at the ortho position by CH2NHCH3.

4. The compound according to claims 1-3, wherein R 1 Selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and NR 17 R 18 , in R 10 Selected from NC(O)C 1-6 Alkyl, H, N(C) 1-6 Alkyl)(C 1-6 alkyl), R 11 Selected from C 1-6 Alkyl, C(O)C 1-6 Alkyl, C 1-6 Alkyl-OC 1-6 Alkyl, OH and OC 1-6 alkyl, R 12 Selected from NHC(O)C 1-6 Alkyl, C 1-6 Alkyl, H, R 13 Selected from NHC(O)C 1-6 Alkyl, C 1-6 Alkyl, H, R 14 Selected from halogens, OH, OC 1-6 Alkyl, H, R 15 Selected from halogens, OH, OC 1-6 Alkyl, H, R 16 Selected from C(O)C 1-6 alkyl, R 17 Selected from C 1-6 Alkyl, H, Ph R 18 Selected from C 1-6 Alkyl, H, Ph R 19 Selected from C(O)C 1-6 alkyl, R 20 It is OH. R 21 Selected from CH3 or H, R 22 Selected from C 1-6 Alkyl, H, C(O)C 1-6 Alkyl groups and C(O)NHC 1-6 alkyl, R 23 Selected from C 1-6 Alkyl and H, R 24 It is C(O)C 1-6 alkyl.

5. The compound according to claim 4, wherein R 1 Selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 and NR 17 R 18 , in R 10 Selected from NC(O)CH3, H, N(CH3)2, R 11 Selected from CH3, C(O)CH3, CH2-OCH3, OH, R 12 Selected from NHC(O)CH3, CH3, H, R 13 Selected from NHC(O)CH3, CH3, H, R 14 Selected from F, OH and H, R 15 Selected from F, OH and H, R 16 Selected from C(O)CH3, R 17 Selected from CH3, H and Ph, R 18 Selected from CH3, H and Ph, R 19 Selected from C(O)CH3, R 20 It is OH. R 21 Selected from CH3 or H, R 22 Selected from CH3, H, C(O)CH3 and C(O)NHCH3, R 23 Selected from CH3 and H, R 24 It is C(O)CH3.

6. The compound according to claim 5, wherein R1 is selected from... and R 14 It's H. R 15 It is OH.

7. The compound according to any of the preceding claims, wherein X is N or CR 25 , where R 25 It's H.

8. The compound according to claims 1-7, used as a drug.

9. Use of the compounds according to claims 1-7 in the treatment of pain.

10. The use according to claim 9, wherein the pain includes acute pain, chronic pain, inflammatory pain, nociceptive pain, neuropathic pain, hyperalgesia, anomalous pain, central pain, cancer pain, postoperative pain, visceral pain, musculoskeletal pain, cardiac or vascular pain, headache, maxillofacial pain, and back pain.

11. Use of the compounds according to claims 1-7 in the treatment of cancer.

12. The use according to claim 11, wherein the cancer is selected from pancreatic cancer, lung cancer, colorectal cancer, bile duct cancer, multiple myeloma, melanoma, uterine cancer, endometrial cancer, thyroid cancer, acute myeloid leukemia, bladder cancer, bladder epithelial cancer, gastric cancer, cervical cancer, head and neck squamous cell carcinoma, diffuse large B-cell lymphoma, esophageal cancer, chronic lymphocytic leukemia, hepatocellular carcinoma, breast cancer, ovarian cancer, prostate cancer, glioblastoma, renal cancer, and sarcoma.

13. Use of the compounds according to claims 1-7 in the treatment of neurofibromatosis.

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