COMPOUNDS, COMPOSITIONS, AND METHODS FOR MODULATING

ANDROGEN RECEPTOR ACTIVITY

FIELD

The disclosure provides for compounds or salts thereof that modulate the activity of the androgen receptor (AR), alternatively referred to herein as MYC/AR-r elated co-factor (MARC), pharmaceutical compositions comprising such compounds or salts thereof, and methods of using the compounds or salts and/or pharmaceutical compositions for treatment, amelioration, and/or prevention of diseases arising from MYC/AR activity and MYC transcriptional complexes, e.g., prostate cancer.

BACKGROUND

Prostate cancer tumors develop resistance to current treatments, especially in therapies that involve targeting the androgen receptor (AR). Treatments generally rely upon continual androgen deprivation therapy via direct AR antagonism (e.g.,

enzalutamide, bicalutamide) or decrease in adrenal androgen production (e.g, abiraterone acetate).

However, acquired resistance to these treatments potentially leads to castration- resistant prostate cancer (CRPC). Studies of CRPC demonstrate that despite low levels of circulating androgens, AR-mediated gene expression is often maintained by AR splice variants (AR-vs) that do not rely upon androgen signaling. Yuan et al. (2009) Urol Oncol , 27: 36-41. Due to variations in their C-terminus, these AR-vs are commonly

constitutively active and effectively mimic full-length AR (AR-FL) in their ability to transactivate androgen response elements (ARE) without androgen stimulation. Watson et al. (2015 ) Nat Rev Cancer , 15: 701-711.

AR-FL is a steroid receptor transcription factor composed of a N-terminal domain (NTD), a DNA binding domain (DBD), and a C-terminal domain (CTD) comprising a hinge region and a ligand binding domain (LBD). Dehm et al. (2007) Mol Endocrinol , 21: 2855-2863. In order for AR-FL to translocate to the nucleus to participate in mechanisms controlling gene expression, an androgen binds to the LBD and induces a structural change to expose the nuclear localization signal (NLS), which initiates importation into the nucleus. Drugs such as enzalutamide act in a mechanism that targets the LBD and thus prevents nuclear translocation and AR-mediated gene expression. Androgen receptor splice variants (AR-vs) arise from alternative splicing of the AR gene by insertion of "intronic" cryptic exons downstream of exons that encode the DNA-binding domain, thereby preventing ligand binding domain (LBD) incorporation and resulting in a shortened AR construct characterized by ligand-independent function. Hu et al. (2009) Cancer Res, 69: 16-22; Guo et al. (2009) Cancer Res, 69: 2305-2313; Dehm et al. (2008) Cancer Res, 68: 5469-5477. AR-vs have a basal level of nuclear localization and remain capable of transcriptional activity even in the absence of the LBD. Chan et al. (2012) J Biol Chem, 287: 19736-19749. This loss of the LBD, in turn, provides a resistance pathway for current prostate cancer drug regimens.

Of the 20 known AR-v isoforms, AR-v7 is the most widely identified and clinically important variant in prostate cancer. Sun et al. (2010 ) J Clin Invest, 120: 2715- 2730; Lu et al. (2015) Nature Rev, 12: 137-144.

AR-v7 is characterized by an unperturbed NTD and DBD with a portion of the NLS and a unique 16-amino acid sequence in its CTD derived from a cryptic exon incorporation. Hu et al. (2009) Cancer Res, 69: 16-22; Guo et al. (2009) AR-v7 is constitutively active in the absence of androgens and can form homodimers and heterodimers with AR-FL to promote canonical AR-mediated gene expression, while also providing an expression profile unique to that of AR-FL, which includes expression of the prostate cancer relevant oncogene AKT1. Le Page et al. (2006) Br J Cancer, 94: 1906- 1912; Ciccarese et al. (2016) Cancer Treat Rev, 43: 27-35.

Single-cell RNA-sequence analysis on circulating tumor cells (CTCs) revealed that approximately 43% of CTCs patients with CRPC expressed at least one type of AR splice variant, wherein AR-v7 and ARv567es (AR-vl2) were the most prominently expressed. Miyamoto et al. (2015) Science, 349: 1351-1356.

Additionally, the AR-v7 expression level in primary tumor cells derived from metastatic prostate cancer and CRPC patients is significantly higher than that in cells derived from patients with localized prostate cancer, and consequently higher AR-v7 expression can be correlated to shorter survival likelihood in CRPC patients (p < 0.001). Qu et al. (2015) Sci Rep, 5: doi: 10.1038/srep07654.

Transcription factors that become overactive in cancers are promising yet untested targets for cancer therapeutics. Koehler A. N. (2010) Curr Opin Chem Bio, 14: 331-340; Darnell, J. E. (2002); Nat Rev Cancer, 2: 740-749. These proteins mediate the excessive transcription of genes whose products are required for tumor growth and metastasis. In particular, prostate cancer progression is often driven by deregulation events affecting transcription factors such as ETS (E26 transformation-specific) family members and AR Baena et al. (2013) Genes Dev, 27: 683-698; Chen et al. (2013) Nat Med, 19: 1023-1029; Dehm et al. (2011) Endocr Relat Cancer, 18: R183-R196; Knudsen et al. (2010) Trends Endocrinol Metab, 21: 315-324. Directly modulating the function of a transcription factor requires disruption or recruitment of DNA-protein or protein-protein interactions. In addition, these transcription cofactors can modulate the activity of transcriptional complexes related to oncogenes such as MYC. Hann et. al., Cold Spring Harb Perspect Med. 2014 Sep; 4(9): a014399.

The discovery or design of small molecules that specifically disrupt or promote these interactions has thus far proven to be a significant challenge, and the protein class is often perceived to be difficult to drug. General and systematic strategies for discovery direct probes of transcription factors remain elusive. Berg T. (2008) Curr Opin Drug Disc Devel, 11: 666-614, Erkizan et al. (2009) Nat Med, 15: 750-756; Ng et al. (2007) Angew Chem Int Ed Engl, 46: 5352-5325; Hammoudeh et al. (2009) J Am Chem Soc, 131: 7390- 7401.

Due to the limitations of current therapies for treating metastatic and castration- resistant prostate cancer (CRPC), there remains a need for drugs that target AR-vs.

SUMMARY

In an embodiment, the disclosure provides for thienopyrimidines, and derivatives thereof, that are inhibitors of androgen receptor transcriptional activity and MYC/AR- related transcriptional complexes.

In an embodiment, the disclosure provides for a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is a C3-C6 saturated or unsaturated ring, optionally aromatic, optionally

heterocyclic, optionally forming a fused, spiro, or bridged ring system with 1 to 8 additional ring atoms, wherein 1 to 4 non-adjacent ring atoms may independently be replaced by N, O, or S, and optionally ring atoms independently may be substituted at any position with one or more D, halo, N(R ² ) ₂ , OR ² or SR ² wherein R ² is C1-C3 alkyl, or C1-C2 alkyl optionally substituted with one or more D or F;

W ¹ is (CFh) _n wherein n is an integer from 0 to 3;

W ² is O or NR ⁸ , wherein R ⁸ is H, C1-C3 alkyl or alkoxy, or R ⁸ forms a fused or spiro ring with W ¹ or R ¹ ;

R ³ is H or C1-C4 alkyl, cycloalkyl, alkoxy, hydroxymethyl, or NR ³ 2, wherein each R ³ is independently H or methyl;

R ⁴ is H or C1-C4 alkyl, cycloalkyl, or alkoxy;

R ⁵ is a 5- or 6-membered aromatic or heteroaromatic ring, attached at any position of the ring, optionally having one or more fused or spiro C4-C6 aromatic, heteroaromatic, aliphatic, or heteroaliphatic rings, and optionally substituted at one or more positions with one or more D, halo, NFh, NHR ⁹ , OH, OR ⁹ , SH, or SR ⁹ , wherein R ⁹ is C1-C4 alkyl, cycloalkyl or alkoxy; and

R ⁶ is H or C1-C4 alkyl, cycloalkyl, or alkoxy.

In another embodiment, W ¹ is absent or W ¹ is (CH2) _n wherein n is an integer from 0 to 3, optionally substituted with methyl, halogen, or hydroxyl, and W ² is absent or W ² is O or NR ⁸ , wherein R ⁸ is H, C1-C3 alkyl or alkoxy, or R ⁸ forms a fused or spiro ring with W ¹ or R ¹ . In another embodiment, W ¹ and W ² together are (CH2) _n O or 0(CH ₂ ) _n wherein n is an integer from 0 to 3, and R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are as defined above.

In yet another embodiment, W ¹ is O and W ² is (CH2) _n wherein n is an integer from 0 to 3, optionally substituted with methyl, halogen, or hydroxyl, and R ¹ , R ³ , R ⁴ , R ⁵ , and R ⁶ are as defined above.

The compound may be in the form of a composition including a pharmaceutically acceptable carrier.

In another embodiment, the disclosure provides for methods of treating, preventing, or ameliorating prostate cancer, including metastatic prostate cancer and castration-resistant prostate cancer (CRPC), by administering an effective amount of a compound or salt of formula (I), or a composition thereof, to a subject in need thereof. DETAILED DESCRIPTION

In an embodiment, a compound described herein capable of use in compositions or methods described herein comprises, consists of, or consists essentially of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In an aspect, the composition is formulated in a pharmaceutical composition or form.

In an embodiment, in the compound or salt thereof of formula (I), R ¹ is a C3-C6 cycloalkyl, optionally substituted with one or more D or halo;

W ¹ is (CH2) _n wherein n is 1;

W ² is O or NH;

R ³ is methyl, ethyl, cyclopropyl, hydroxymethyl, or NR ³ 2, wherein each R ³ is independently H or methyl;

R ⁴ is C1-C4 alkyl;

R ⁵ is pyridyl or quinolyl, optionally substituted at any position with methoxy, ethoxy, or C1-C4 alkyl; and

R ⁶ is H or methyl.

In another embodiment, in the compound or salt thereof of formula (I), R ¹ is cyclopentyl optionally substituted at the 2 or 3 position with one or two F, or R ¹ is cyclohexyl optionally substituted at the 2 or 4 position with one or two F; n is 1; R ³ is methyl or ethyl; R ⁴ is methyl or ethyl; and R ⁵ is pyridyl optionally substituted at one or more positions with one or more methyl or methoxy.

In yet another embodiment, R ¹ is cyclopentyl optionally substituted at the 2 or 3 position with one or two F, or R ¹ is cyclohexyl optionally substituted at the 2 or 4 position with one or two F; R ⁵ is pyridyl optionally substituted at one or more positions with one or more methyl or methoxy; and R ⁶ is H or methyl.

Examplary compounds are shown in a Table herein as compounds 1 to 151. Any of the compounds described via formula (I) or shown as specific compounds may be a single stereoisomer or a mixture of possible stereoisomers. For example, if a single chiral carbon is present, the compound may be the (S) or (R) stereoisomer, with respect to the chiral carbon, or the compound may be a non-racemic mixture of (S) and (R) isomers, or the compound may be the (S) isomer alone or the (R) isomer alone. If the compound contains more than one chiral carbon, the compound may be a single diastereomer or a mixture of diastereomers.

By“salt” is meant a pharmaceutically acceptable salt, e.g., a hydrochloride salt. A “pharmaceutically acceptable salt” is a salt that retains the activity of the compound without significant adverse effects. Examples of pharmaceutically acceptable salts include salts of organic or inorganic acids, e.g., hydrochloric acid, sulphuric acid,

methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, trifluoroacetic acid, and formic acid. The salt may contain one or more equivalents of acid per compound, i.e., the compound may be in the form of a dichloride salt.

The active compounds disclosed can also be in the form of their hydrates. The term“hydrate” includes, e.g., hemihydrate, monohydrate, dihydrate, trihydrate, and tetrahydrate.

The compounds of this disclosure may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure includes all suitable isotopic variations of the compounds described herein.

“Alkyl” means branched and straight-chain saturated aliphatic hydrocarbons, and specifying the number of carbon atoms as in“C1-C6 alkyl” means all isomers thereof having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement. Thus,“C1-C6 alkyl” includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, etc.

“Cycloalkyl” means cyclic saturated aliphatic hydrocarbons of the specified number of carbons.

“D” is deuterium.

“Halo” means a halogen substituent, e.g., F, Cl, or Br.

An“effective amount” or“therapeutically effective amount” is an amount of the compound or composition that is sufficient to effect beneficial or desired results as described herein when administered to a subject. Effective dosage forms, modes of administration, and dosage amounts may be determined empirically, and making such determinations is within the skill of the art. It is understood by those skilled in the art that the dosage amount will vary with the route of administration, the rate of excretion, the duration of the treatment, the identity of any other drugs being administered, the age, size, and species of mammal, e.g., human patient, and like factors well known in the arts of medicine and veterinary medicine. In general, a suitable dose will be that amount of the compound that is the lowest dose effective to produce the desired effect with no or minimal side effects.

A suitable, non-limiting example of a dosage of the compounds according to the present disclosure is from about 1 ng/kg to about 1000 mg/kg, such as from about 1 mg/kg to about 100 mg/kg, including from about 5 mg/kg to about 50 mg/kg. Other representative dosages of a PI3K inhibitor include about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg.

Yet another embodiment of the present disclosure is a pharmaceutical composition for treating an AR-mediated disease. The AR-mediated disease may be a prostate cancer, including metastatic prostate cancer and castration-resistant prostate cancer (CRPC).

The pharmaceutical composition may include a pharmaceutically acceptable carrier and an effective amount of the compounds described herein.

A pharmaceutical composition of the present disclosure may be administered in any desired and effective manner: for oral ingestion, or as an ointment or drop for local administration to the eyes, or for parenteral or other administration in any appropriate manner such as intraperitoneal, subcutaneous, topical, intradermal, inhalation,

intrapulmonary, rectal, vaginal, sublingual, intramuscular, intravenous, intraarterial, intrathecal, or intralymphatic. Further, a pharmaceutical composition of the present disclosure may be administered in conjunction with other treatments. A pharmaceutical composition of the present disclosure maybe encapsulated or otherwise protected against gastric or other secretions, if desired.

The pharmaceutical compositions of the disclosure are pharmaceutically acceptable and comprise one or more active ingredients in admixture with one or more pharmaceutically-acceptable carriers and, optionally, one or more other compounds, drugs, ingredients and/or materials. Regardless of the route of administration selected, the agents/compounds of the present disclosure are formulated into pharmaceutically- acceptable dosage forms by conventional methods known to those of skill in the art using pharmaceutically acceptable carriers well-known in the art (see, e.g., Remington, The Science and Practice of Pharmacy (21st Edition, Lippincott Williams and Wilkins, Philadelphia, Pa.) and The National Formulary (American Pharmaceutical Association, Washington, D.C.)) and include sugars (e.g., lactose, sucrose, mannitol, and sorbitol), starches, cellulose preparations, calcium phosphates (e.g., dicalcium phosphate, tricalcium phosphate and calcium hydrogen phosphate), sodium citrate, water, aqueous solutions (e.g., saline, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection, lactated Ringer's injection), alcohols (e.g., ethyl alcohol, propyl alcohol, and benzyl alcohol), polyols (e.g., glycerol, propylene glycol, and polyethylene glycol), organic esters (e.g., ethyl oleate and tryglycerides), biodegradable polymers (e.g., polylactide-polyglycolide, poly(orthoesters), and poly(anhydrides)), elastomeric matrices, liposomes, microspheres, oils (e.g., com, germ, olive, castor, sesame, cottonseed, and groundnut), cocoa butter, waxes (e.g., suppository waxes), paraffins, silicones, talc, silicylate, etc. Each pharmaceutically acceptable carrier used in a pharmaceutical composition of the disclosure is "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Carriers suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable carriers for a chosen dosage form and method of administration can be determined using ordinary skill in the art.

The pharmaceutical compositions of the disclosure may, optionally, contain additional ingredients and/or materials commonly used in such pharmaceutical compositions. These ingredients and materials are well known in the art and include (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, sucrose and acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium

carboxymethyl cellulose and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, and sodium lauryl sulfate; (10) suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth; (11) buffering agents; (12) excipients, such as lactose, milk sugars, polyethylene glycols, animal and vegetable fats, oils, waxes, paraffins, cocoa butter, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonites, silicic acid, talc, salicylate, zinc oxide, aluminum hydroxide, calcium silicates, and polyamide powder;

(13) inert diluents, such as water or other solvents; (14) preservatives; (15) surface-active agents; (16) dispersing agents; (17) control-release or absorption-delaying agents, such as hydroxypropylmethyl cellulose, other polymer matrices, biodegradable polymers, liposomes, microspheres, aluminum monosterate, gelatin, and waxes; (18) opacifying agents; (19) adjuvants; (20) wetting agents; (21) emulsifying and suspending agents; (22), solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan; (23) propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane; (24) antioxidants; (25) agents which render the formulation isotonic with the blood of the intended recipient, such as sugars and sodium chloride; (26) thickening agents; (27) coating materials, such as lecithin; and (28) sweetening, flavoring, coloring, perfuming and preservative agents. Each such ingredient or material must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject. Ingredients and materials suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable ingredients and materials for a chosen dosage form and method of administration may be determined using ordinary skill in the art.

Pharmaceutical compositions suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules, a solution or a suspension in an aqueous or non-aqueous liquid, an oil-in-water or water-in-oil liquid emulsion, an elixir or syrup, a pastille, a bolus, an electuary or a paste. These formulations may be prepared by methods known in the art, e.g., by means of conventional pan-coating, mixing, granulation or lyophilization processes.

Solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like) may be prepared, e.g., by mixing the active ingredient(s) with one or more pharmaceutically-acceptable carriers and, optionally, one or more fillers, extenders, binders, humectants, disintegrating agents, solution retarding agents, absorption accelerators, wetting agents, absorbents, lubricants, and/or coloring agents. Solid compositions of a similar type maybe employed as fillers in soft and hard-filled gelatin capsules using a suitable excipient. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using a suitable binder, lubricant, inert diluent, preservative, disintegrant, surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine. The tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein. They may be sterilized by, for example, filtration through a bacteria-retaining filter. These compositions may also optionally contain opacifying agents and may be of a composition such that they release the active ingredient only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. The active ingredient can also be in microencapsulated form.

Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. The liquid dosage forms may contain suitable inert diluents commonly used in the art. Besides inert diluents, the oral compositions may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents. Suspensions may contain suspending agents.

Pharmaceutical compositions for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more active ingredient(s) with one or more suitable nonirritating carriers which are solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound. Pharmaceutical compositions which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such pharmaceutically-acceptable carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, drops and inhalants. The active agent(s)/compound(s) may be mixed under sterile conditions with a suitable pharmaceutically-acceptable carrier. The ointments, pastes, creams and gels may contain excipients. Powders and sprays may contain excipients and propellants.

Pharmaceutical compositions suitable for parenteral administrations comprise one or more agent(s)/compound(s) in combination with one or more pharmaceutically- acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain suitable antioxidants, buffers, solutes which render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents. Proper fluidity can be maintained, for example, by the use of coating materials, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain suitable adjuvants, such as wetting agents, emulsifying agents and dispersing agents. It may also be desirable to include isotonic agents. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption.

In some cases, to prolong the effect of a drug (e.g., pharmaceutical formulation), it is desirable to slow its absorption from subcutaneous or intramuscular injection. This may be accomplished by use of a liquid suspension of crystalline or amorphous material having poor water solubility.

The rate of absorption of the active agent/drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.

Alternatively, delayed absorption of a parenterally-administered agent/drug may be accomplished by dissolving or suspending the active agent/drug in an oil vehicle.

Injectable depot forms may be made by forming microencapsule matrices of the active ingredient in biodegradable polymers. Depending on the ratio of the active ingredient to polymer, and the nature of the particular polymer employed, the rate of active ingredient release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue. The injectable materials can be sterilized for example, by filtration through a bacterial- retaining filter.

The formulations may be presented in unit-dose or multi -dose sealed containers, for example, ampules and vials, and may be stored in a lyophilized condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the type described above.

As used herein, a“subject” is a mammal, e.g., a human. In addition to humans, categories of mammals within the scope of the present disclosure include, for example, agricultural animals, domestic animals, laboratory animals, etc. Some examples of agricultural animals include cows, pigs, horses, goats, etc. Some examples of domestic animals include dogs, cats, etc. Some examples of laboratory animals include rats, mice, rabbits, guinea pigs, etc.

As used herein, the terms“treat,”“treating,”“treatment” and grammatical variations thereof mean subjecting an individual subject to a protocol, regimen, process or remedy, in which it is desired to obtain a physiologic response or outcome in that subject, e.g., a patient. In particular, the methods and compositions of the present disclosure may be used to slow the development of disease symptoms or delay the onset of the disease or condition, or halt the progression of disease development. However, because every treated subject may not respond to a particular treatment protocol, regimen, process or remedy, treating does not require that the desired physiologic response or outcome be achieved in each and every subject or subject, e.g., patient, population. Accordingly, a given subject or subject, e.g., patient, population may fail to respond or respond inadequately to treatment.

As used herein, the terms“ameliorate”,“ameliorating” and grammatical variations thereof mean to decrease the severity of the symptoms of a disease in a subject.

As used herein, the terms“prevent”,“preventing” and grammatical variations thereof mean to administer a compound or composition of the present disclosure to a subject who has not been diagnosed as having the disease or condition at the time of administration, but who could be expected to develop the disease or condition or be at increased risk for the disease or condition. Preventing also includes administration of at least one compound or a composition of the present disclosure to those subjects thought to be predisposed to the disease or condition due to age, familial history, genetic or chromosomal abnormalities, due to the presence of one or more biological markers for the disease or condition and/or due to environmental factors.

The following examples serve to illustrate certain aspects of the disclosure and are not intended to limit the disclosure. EXAMPLES

The following examples describe preparation and testing of representative compounds.

Example 1:

Scheme 1 shows a synthetic process for making embodiments of formula (I).

Scheme 1

Step 1

To a stirred solution of ethyl 2-cyanoacetate (23.52 mL, 221.02 mmol) and ethyl 3-oxobutanoate (28.2 mL, 221.02 mmol) in ethanol (250 mL) was added sulfur powder (7.07 g, 221.02 mmol), followed by dropwise addition of diethylamine (22.86 mL, 221.02 mmol). The reaction was then stirred for 16h at ambient temperature. After this time, the solvent was removed under reduced pressure, and the crude residue diluted with ethyl acetate (240 ml). The organic phase was washed with water (60 mL x 2), followed by saturated NaCl solution (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a crude material, which was purified by silica gel chromatography to yield diethyl 5-amino-3-methyl-thiophene-2,4- di carboxyl ate (35.0 g, 136.02 mmol, 62% yield). ¾ NMR (400 MHz, DMSO-^e): d 7.91 (br s, 2H), 4.13-4.24 (m, 4H), 2.59 (s, 3H), 1.18-1.32 (m, 6H). MS (ESI+) [M-H] : 256.0 (ACN: MLOAc).

Step 2

Diethyl 5 -amino-3 -methyl-thiophene-2, 4-dicarboxylate (10.0 g, 38.86 mmol) was added to a solution of formamide (50.0 mL, 1255.6 mmol) and acetic acid (0.50 mL,

38.86 mmol), which was subsequently heated at 160° C for 12 h. After the reaction was deemed complete, the reaction was quenched with ice water, and the precipitated solid was collected by filtration. After washing with water, the solid product was dried under reduced pressure to afford ethyl 4-hydroxy-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (7.97 g, 33.46 mmol, 86 % yield). ¾ NMR (400 MHz, DMSO-^e) d 12.52 (s, 1H), 8.20 (s, 1H), 4.26-4.32 (q, J= 7.1 Hz, 2H), 2.80 (s, 3H), 1.28-1.31 (t, 7= 7.1 Hz,

3H). MS (ESI) [M+H] ⁺ : 239.2 (ACN: NH ₄ OAc).

Step 3

To a stirred solution of ethyl 4-hydroxy-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (30.0 g, 125.91 mmol) in POCh (35.31 mL, 377.74 mmol) was added PCb (3.78 g, 62.96 mmol) at ambient temperature. The reaction was then heated to 110 °C for 12 h. After this time, the reaction was quenched with cold water (100 mL) and then neutralized with saturated sodium bicarbonate solution (50 mL). The crude reaction mixture was extracted with ethyl acetate (2 x 250 mL), followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (10% ethyl acetate/hexane) to afford ethyl 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (27.0 g, 105.18 mmol, 84% yield) as a yellow solid. ¾ NMR (400 MHz, DMSO-7 ₆ ) d 9.03 (s, 1H), 4.36-4.41 (q, = 7.1 Hz, 2H), 2.98 (s, 3H), 1.32-1.36 (t , J= 7.1 Hz, 3H). MS (ESI) [M+H] ⁺ : 257.0 (ACN:NH ₄ OAc).

Example 2:

Scheme 2 shows a synthetic process for making embodiments of formula (I).

Scheme 2

Step 1

To a stirred solution of methyl 4-hydroxy-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (26.0 g, 115.95 mmol) in a mixture of THF (260 mL) and Water (130 mL) at 0 °C was added LiOH monohydrate (14.6 g, 347.84 mmol). The reaction mixture was stirred at ambient temperature for 16h. After the reaction was complete, the reaction was concentrated under vacuum, diluted with water (30 mL), and acidified with IN HC1. The heterogeneous mixture was extracted with EtOAc (2 x 300 ml), and the combined organic extracts concentrated under reduced pressure to yield 4-hydroxy-5-methyl-thieno[2,3- d]pyrimidine-6-carboxylic acid (19.5 g, 92.662 mmol, 80% yield) as off white solid. ¾ NMR (400 MHz, DMSO-^e) d 12.59 (br, 1H), 8.18 (s, 1H), 2.80 (s, 3H). MS (ESI)

[M+H] ⁺ : 211.2 (ACN: HCOOH).

Step 2

To a stirred solution of 4-hydroxy-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (5.0 g, 23.79 mmol) and l-(2-methoxypyridin-4-yl)-N-methylmethanamine (2905.9 mg, 23.79 mmol) in DMF (54 mL) were added N,N-diisopropylethylamine (10.34 mL, 59.46 mmol), EDC.HC1 (5.45 g, 28.54 mmol), and HOBt (3.85 g, 28.54 mmol) at 0° C under an atmosphere of N2. The reaction was warmed to ambient temperature and let stir for 16h. After this time, the reaction mixture was quenched with cold water and extracted with CH2CI2 (500 mL x 4). The combined organic phase was washed with saturated NaCl solution (200 mL), followed by drying over anhydrous sodium sulfate. The organic phase was filtered and solvent removed to afford the crude product, which was purified by column chromatography (Combi-flash 230-400 silica gel, EtOAc / CH2CI2) to produce 4- hydroxy-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3-d]pyrimidine-6- carboxamide (4.2g, 12.20 mmol, 51 % yield). 1H NMR (400 MHz, DMSO-d6) d 12.56 (br, 1H), 8.13-8.15 (m, 2H), 6.86 (s, 1H), 6.66 (s, 1H), 4.62 (s, 2H), 3.84 (s, 3H), 2.94 (s, 3H), 2.44 (s, 3H). MS (ESI) [M+H] ⁺ : 345.3 (ACN: Formic Acid).

Step 3

To a stirred solution of 4-hydroxy-N-[(2-methoxy-4-pyridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (1.50 g, 4.36 mmol) in POCb (1.22 mL, 13.07 mmol) was added PCI5 (452.97 mg, 2.18 mmol) at ambient temperature. The reaction was then heated to 110 °C for 4 h. After this time, the reaction was quenched with cold water (10 mL) and neutralized with saturated aqueous sodium bicarbonate solution (10 mL). The crude mixture was extracted with CH2CI2 (2 x 50 mL) and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to afford 4-chloro-N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (1.00 g, 2.76 mmol, 63% yield), which was used without further purification. 1H NMR (400 MHz, DMSO-6/6): d 8.96 (s, 1H), 8.13-8.18 (m, 1H), 6.59-6.95 (m, 2H), 4.70 (s, 2H), 3.86 (s, 3H), 2.94-2.99 (m, 3H), 2.56 (s, 3H). MS (ESI) [M+H] ⁺ : 363.2 (ACN:NH ₄ OAc).

Example 3:

Scheme 3 shows a synthetic process for making embodiments of formula (I).

Scheme 3

Step 1

To a stirred solution of ethyl propionyl acetate (500mg, 3.47 mmol) in ethanol (10 mL) were added sulfur powder (110.98 mg, 3.47 mmol), ethyl 2-cyanoacetate (392.28 mg, 3.47 mmol), and diethylamine (0.36 mL, 3.47 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 16 h. After this time, the reaction mixture was concentrated and diluted with ice water. The mixture was extracted with ethyl acetate (2 x 80mL), the combined organics washed with brine (30 mL) and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the crude product was purified by silica gel chromatography (5% ethyl acetate / hexane) to afford diethyl 5- amino-3-ethyl-thiophene-2,4-dicarboxylate (320 mg, 1.1794 mmol, 34% yield). 1H NMR (400 MHz, DMSO-d6) d 7.93 (s, 2H), 4.11-4.28 (m, 4H), 3.17 (q, J = 7.3 Hz, 2H), 1.17- 1.32 (m, 6H), 1.07 (t, J = 7.2 Hz, 3H). MS (ESI) [M+H] ⁺ 272.0 (ACN: MLOAc).

Step 2

To a stirred solution of diethyl 5-amino-3-ethyl -thiophene-2, 4-dicarboxylate (1.0 g, 3.69 mmol) in acetic acid (0.3 mL, 1.84 mmol) was added formamide (4.0 mL, 14.74 mmol), and the reaction heated at 160 °C for 12h. After this time, the reaction was cooled to ambient temperature and ice water added. The precipitated solid was collected by filtration, washed with water, then dried under reduced pressure to afford ethyl 5- ethyl-4-hydroxy-thieno[2,3-d]pyrimidine-6-carboxylate (320 mg, 1.2684 mmol, 34% yield) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6) d 12.65 (s, 1H), 8.22 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.37 (q, J = 7.3 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H), 1.15 (t, J = 7.3 Hz, 3H). MS (ESI) [M+H] 253.0 (ACN: MLOAc)

Step 3

To a stirred solution of ethyl 5-ethyl-4-hydroxy-thieno[2,3-d]pyrimidine-6- carboxylate (400.0 mg, 1.59 mmol) in POCh (4.45 mL, 47.56 mmol) was added PCb (331 mg, 1 59mmol), and the reaction mixture heated at 100° C for 12 h. After this time, the reaction mixture was cooled to ambient temperature, and made basic with saturated NaHCCL solution. This was extracted with ethyl acetate (80 ml x 2), and the combined organic layers washed with brine. After evaporating to dryness, the crude organic solid was triturated with pentane to afford ethyl 4-chloro-5-ethyl-thieno[2,3-d]pyrimidine-6- carboxylate (200 mg, 0.7387 mmol, 46.6% yield) as brown solid. ¾ NMR (400 MHz, DMSO-d6) d 9.05 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 3.51 (q, J = 7.4 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.4 Hz, 3H). MS (ESI) [M+H] ⁺ 271.0 (ACN: MEOAc).

Example 4:

Scheme 4 shows a synthetic process for making embodiments of formula (I).

Step 1

To a stirred solution of N,N-diisopropylamine (1731.78 mg, 13.42 mmol) in THF (30 mL) was added 2.8 M «-BuLi (4.79 mL, 13.42 mmol) at -78 °C. The reaction mixture was then warmed to 0° C and stirred for 30 min. At this point, the LDA solution was cooled to -78°C, and a solution of 4,6-dichloropyrimidine (2.0 g, 13.42 mmol) in THF (15 mL) was added dropwise. After stirring at this temperature for 45 min, a solution of 2- benzyloxyacetaldehyde (2.05 mL, 14.77 mmol) in THF (15 mL) was added to the reaction mixture at -78°C, and stirred for lh. The reaction mixture was quenched by the addition of water, and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was washed with brine (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (5% ethyl acetate / hexane) to afford 2-benzyloxy-l-(4,6-dichloropyrimidin-5-yl)ethanol (900 mg, 3.0085 mmol, 22% yield). MS (ESI) [M+H] ⁺ 299.3 (ACN: MLOAc).

Step 2

To a stirred solution of 2-benzyloxy-l-(4,6-dichloropyrimidin-5-yl)ethanol (5.0 g, 16.71 mmol) in CH2CI2 (50mL) was added dess martin periodinane (10.63 g, 25.07 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h, after which time the reaction mass was quenched with sodium bicarbonate solution and extracted with CH2CI2 (2 x 250 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (5% ethyl acetate in hexane) to afford 2-benzyloxy-l-(4,6- dichloropyrimidin-5-yl)ethanone (2 g, 6.7308 mmol, 40% yield). 1H NMR (400 MHz, DMSO-d6) d 9.07 (s, 1H), 7.29-7.39 (m, 5H), 4.61-4.66 (m, 4H). MS (ESI) [M+H] ⁺ 297.4 (ACN: NH ₄ OAc).

Step 3

To a stirred solution of 2-benzyloxy-l-(4,6-dichloropyrimidin-5-yl)ethanone (2.0 g, 6.73 mmol) in CH2CI2 (25 mL) was added NEt3 (2.83 mL, 20.19 mmol), followed by ethyl 2-sulfanylacetate (0.6 mL, 5.05 mmol) at -78° C. The reaction was stirred at same temperature for 1 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 200 mL). Organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography to yield ethyl 2-[5-(2-benzyloxyacetyl)-6-chloro-pyrimidin-4- yljsulfanylacetate (600 mg, 1.5754 mmol, 23% yield). 1H NMR (400 MHz, DMSO-d6) d 7.29-7.36 (m, 5H), 4.59-4.66 (m, 2H), 4.06-4.16 (m, 4H), 1.13-1.18 (m, 6H). LCMS: 381.0 [M+H] (ACN: NH ₄ OAc).

Step 4

To a stirred solution of ethyl 2-[5-(2-benzyloxyacetyl)-6-chloro-pyrimidin-4- yljsulfanylacetate (300.0 mg, 0.7900 mmol) in CH2CI2 (5 mL) at -10 °C was added DBU (0.33 mL, 2.36 mmol). The reaction was stirred at this temperature for lh. After completion, the reaction mixture was diluted with water and extracted with CH2CI2 (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (10% ethyl acetate / hexane) to afford ethyl 5-(benzyloxymethyl)-4-chloro-thieno[2,3- d]pyrimidine-6-carboxylate (150 mg, 0.4134 mmol, 52% yield) as a colorless liquid. 1H NMR (400 MHz, DMSO-d6) d 9.07 (s, 1H), 7.25-7.35 (m, 5H), 5.26 (s, 2H), 4.63 (s,

2H), 4.39 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H). MS (ESI) [M+H] ⁺ 363.2 (ACN: NH ₄ OAC).

Step 5

To a stirred solution of ethyl 5-(benzyloxymethyl)-4-chloro-thieno[2,3- d]pyrimidine-6-carboxylate (500.0 mg, 1.38 mmol) in THF (10 mL) was added NEt3 (0.58 mL, 4.13 mmol) followed by (4,4-difluorocyclohexyl)methanamine (0.22 mL, 1.65 mmol) at 0°C. The reaction mixture was stirred at ambient temperature for 16 h. After completion, the reaction was diluted with water and extracted with ethyl acetate (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resultant crude compound was purified by silica gel

chromatography (20% ethyl acetate / hexane). Pure fractions were concentrated under reduced pressure to get ethyl 5-(benzyloxymethyl)-4-[(4,4- difluorocyclohexyl)methylamino]thieno[2,3-d]pyrimidine-6-car boxylate (500 mg, 1.0514 mmol, 76 % yield). 1H NMR (400 MHz, DMSO-d6) d 8.44 (s, 1H), 7.94 (s, 1H), 7.31- 7.36 (m, 5H), 5.33 (s, 2H), 4.62 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.37 (t, J = 6.2 Hz, 2H), 1.84-1.89 (m, 2H), 1.55-1.67 (m, 5H), 1.30 (t, J = 7.1 Hz, 3H), 1.03-1.10 (m, 3H). MS (ESI) [M+H] ⁺ 476.1 (ACN: NH ₄ OAc).

Step 6

To a stirred solution of ethyl 5-(benzyloxymethyl)-4-[(4,4- difluorocyclohexyl)methylamino]thieno[2,3-d]pyrimidine-6-car boxylate (500.0 mg, 1.05 mmol) in ethanol (10 mL) was added 0.2M NaOH solution (5.0 mL, 1.05 mmol) at ambient temperature, and stirred for 2 h. After completion, the reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous solution was acidified with acetic acid, and the precipitated solid filtered and dried under vacuum to yield 5-(benzyloxymethyl)-4-[(4,4-difluorocyclohexyl)methylamino]t hieno[2,3- d]pyrimidine-6-carboxylic acid (350 mg, 0.7821 mmol, 74% yield) as white solid. 1H NMR (400 MHz, DMSO-d6) d 14.02 (brs, 1H), 8.41 (s, 1H), 7.89 (t, J = 5.7 Hz, 1H), 7.29-7.40 (m, 5H), 5.38 (s, 2H), 4.61 (s, 2H), 3.32-3.36 (m, 2H), 1.82-1.86 (m, 2H), 1.51-1.64 (m, 5H), 0.99-1.13 (m, 2H). MS (ESI) [M+H] ⁺ 448.1 (ACN: MLOAc).

Step 7

To a stirred solution of 5-(benzyloxymethyl)-4-[(4,4- difluorocyclohexyl)methylamino]thieno[2,3-d]pyrimidine-6-car boxylic acid (250.0 mg, 0.5600 mmol) in THF (10 mL) were added HATU (424.84 mg, 1.12 mmol), N,N- diisopropylethylamine (0.29 mL, 1.68 mmol) and l-(2-methoxy-4-pyridyl)-N-methyl- methanamine (102 mg, 0.67 mmol) at 0° C. The reaction mixture was then stirred at ambient temperature for 16h. After completion, the reaction mass was quenched with sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resultant crude compound was purified by silica gel

chromatography (5% methanol / CH2CI2) to afford 5-(benzyloxymethyl)-4-[(4,4- difluorocyclohexyl)methylamino]-N-[(2-methoxy-4-pyridyl)meth yl]-N-methyl- thieno[2,3-d]pyrimidine-6-carboxamide (200 mg, 0.3317 mmol, 59% yield) as an off- white solid: 1H NMR (400 MHz, DMSO-d6) d 8.39 (s, 1H), 8.12-8.17 (m, 1H), 7.55- 7.60 (m, 1H), 7.29-7.38 (m, 4H), 6.58-6.89 (m, 2H), 4.76 (s, 2H), 4.59-4.67 (m, 4H),

3.84 (s, 3H), 2.93 (s, 3H), 1.85 (s, 2H), 1.54-1.64 (m, 6H), 1.02-1.11 (m, 2H). [Note: 2H may be merged in solvent peak] MS (ESI) [M+H] ⁺ 581.9 (ACN: MEOAc).

Step 8

To a stirred solution of 5-(benzyloxymethyl)-4-[(4,4- difluorocyclohexyl)methylamino]-N-[(2-methoxy-4-pyridyl)meth yl]-N-methyl- thieno[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.17 mmol) in CH2CI2 (5 mL) was added 1M BCh in CH2CI2 (0.6 mL, 0.69 mmol) at 0° C. The reaction mixture was continued to stir at 0° C for 3 h. After completion, the reaction mass was concentrated under reduced pressure, followed by repeated co-distilled with methanol (2 x 5 mL). The crude product was purified by prep-HPLC, to afford 4-[(4,4- difluorocyclohexyl)methylamino]-5-(hydroxymethyl)-N-[(2-meth oxy-4-pyridyl)methyl]- N-methyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 27) (1.5 mg, 0.0029 mmol,

2% yield). MS (ESI) [M+H] ⁺ 492.5.

The following are examples of analogs prepared according to Scheme 4:

5-(hydroxymethyl)-N-[(2-methoxy-4-pyridyl)methyl]-N-methyl-4 -(3,3,3- trifluoropropylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 87) 4-[(4,4-dichlorocyclohexyl)methylamino]-5-(hydroxymethyl)-N- [(2-methoxy-4- pyridyl)methyl]-N-methyl-thieno[2,3-d]pyrimidine-6-carboxami de (compound 28): 1H MR (400 MHz, DMSO-d6) d 8.49 (d, J = 6.0 Hz, 1H), 8.37 (s, 1H), 8.16 (d, J = 5.1 Hz, 1H), 6.75-6.69 (m, 3H), 4.63 (d, J= 4.7 Hz, 4H), 3.86 (s, 3H), 3.46 (t, J= 5.7 Hz, 2H), 2.94 (s, 3H), 2.46-2.44 (m, 2H), 2.32-2.20 (m, 2H), 1.84-1.76 (m, 3H), 1.52-1.37 (m, 2H). MS (ESI) [M+H] ⁺ : 524.0 (ACN: NH ₄ OAc).

Example 5:

Scheme 5 shows a synthetic process for making embodiments of formula (I).

Scheme 5

Step 1

To a stirred solution of diisopropylamine (3.88 mL, 26.85 mmol) in THF (30 mL) was added 1.68 M n- BuLi (16.0 mL, 26.85 mmol) dropwise at -78° C. The reaction mixture was warmed to 0° C, and stirred at this temperature for 30 min. After this time, a solution of 4,6-dichloropyrimidine (4.0 g, 26.85 mmol) in THF (15 mL) was added to the reaction mixture at -78 °C, and the reaction mixture was stirred at same temperature for 45 min. The solution of cyclopropanecarbaldehyde (1881.86 mg, 26.85 mmol) in THF (15 mL) was added to the reaction mixture at -78 °C, and the stirring continued for lh. After consumption of the starting material, the reaction mixture was diluted with water, and organic part was extracted with ethyl acetate (3 x 100 mL). The organic layer was washed with brine solution (100 mL), dried over sodium sulfate, filtered, and

concentrated under reduced pressure. After purification by silica gel chromatography, fractions containing desired product were concentrated under reduced pressure to afford cyclopropyl-(4,6-dichloropyrimidin-5-yl)methanol (2.0 g, 9.13 mmol, 34% yield). ¾ NMR (400 MHz, DMSO-d6) d 8.82 (s, 1H), 5.72-5.77 (m, 1H), 4.42 (d, J = 9.0 Hz, 1H), 1.54-1.68 (m, 1H), 0.61-0.67 (m, 1H), 0.48-0.55 (m, 1H), 0.37-0.45 (m, 1H), 0.22-0.33 (m, 1H).

Step 2

To a stirred solution of cyclopropyl-(4,6-dichloropyrimidin-5-yl)methanol (400.0 mg, 1.83 mmol) in CH2CI2 (lOmL) was added Dess-Martin periodinane (1.16 g, 2.74 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 4 h. After this time, the reaction mixture was quenched with the addition of saturated sodium

bicarbonate solution. The bi-phasic solution was extracted with ethyl acetate (2 x 100 mL), and the combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (10% ethyl acetate / hexane) to afford cyclopropyl -(4, 6- dichloropyrimidin-5-yl)methanone (250 mg, 1.1518 mmol, 63% yield) as colorless liquid. 1H NMR (400 MHz, DMSO-d6) d 9.04 (s, 1H), 2.50-2.58 (m, 1H), 1.19-1.34 (m, 4H).

Step 3

To a stirred solution of cyclopropyl -(4, 6-dichloropyrimidin-5-yl)methanone (1.5 g, 6.91 mmol) in CH2CI2 (20 mL) was added NEt3 (1.94 mL, 13.82 mmol) followed by ethyl 2-sulfanylacetate (0.66 mL, 5.53 mmol) at -78° C. The reaction was stirred at same temperature for 1 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 20 mL). Organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography to yield ethyl 2-[6-chloro-5-(cyclopropanecarbonyl)pyrimidin- 4-yl]sulfanylacetate (1 g, 3.3249 mmol, 48% yield) as a colorless liquid. ¾NMR (400 MHz, DMSO-d6) d 8.87 (s, 1H), 4.07-4.16 (m, 4H), 1.14-1.32 (m, 8H). MS (ESI)

[M+H] 301.2 (ACN:NH ₄ OAC).

Step 4

To a stirred solution of ethyl 2-[6-chloro-5-(cyclopropanecarbonyl)pyrimidin-4- yljsulfanylacetate (50.0 mg, 0. 1700mmol) in CH2CI2 (5 mL) were added DBU (0.07 mL, 0.50 mmol) at 0° C. The reaction was then warmed to ambient temperature and stirred for lh. After consumption of the starting material, the reaction mixture was diluted with water and extracted with CH2CI2 (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (10% ethyl acetate / hexane) to afford ethyl 4- chloro-5-cyclopropyl-thieno[2,3-d]pyrimidine-6-carboxylate (35 mg, 0.1238 mmol, 74% yield. ¾ NMR (400 MHz, DMSO-d6) d 9.01 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.09-2.21 (m, 1H), 1.35 (t, J = 7.1 Hz, 3H), 1.15-1.21 (m, 2H), 0.65-0.74 (m, 2H). MS (ESI)

[M+H] ⁺ 283.2 (ACN:NH ₄ OAC).

Step 5

To a stirred solution of ethyl 4-chloro-5-cyclopropyl-thieno[2,3-d]pyrimidine-6- carboxylate (0.2 g, 0.7100 mmol) in THF (10 mL) were added NEt3 (0.3 mL, 2.12 mmol) and (4,4-difluorocyclohexyl)methanamine (0.77 mL, 0.8500 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h. After this time, the reaction mixture was diluted with water and extracted with ethyl acetate (2 x 20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (20% ethyl acetate / hexane) to produce ethyl 5-cyclopropyl-4-[(4,4-difluorocyclohexyl)methylamino]thieno[ 2,3- d]pyrimidine-6-carboxylate (200 mg, 0.5057 mmol, 71% yield). 1H NMR (400 MHz, DMSO-d6) d 8.39 (s, 1H), 7.36 (t, J = 5.9 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 3.53 (t, J = 6.4 Hz, 2H), 2.18-2.29 (m, 1H), 1.99-2.07 (m, 2H), 1.70-1.91 (m, 5H), 1.32 (t, J = 7.0 Hz, 4H), 1.21 (d, J = 7.0 Hz, 3H), 0.65 (d, J = 5.5 Hz, 2H). MS (ESI) [M+H] ⁺ 396.0 (ACN: MEOAc).

Step 6

To a stirred solution of ethyl 5-cyclopropyl-4-[(4,4- difluorocyclohexyl)methylamino]thieno[2,3-d]pyrimidine-6-car boxylate (200.0 mg, 0.5100 mmol) in ethanol (5 mL) was added 0.25M NaOH (2.0mL, 0.51 mmol) at 0° C. The reaction mixture was warmed to ambient temperature, and stirred for lh. After completion, the reaction mixture was concentrated under reduced pressure and diluted with water. The aqueous layer was made acidic with acetic acid, and extracted with ethyl acetate (2 x 20 mL). Organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-cyclopropyl-4-[(4,4- difluorocyclohexyl)methylamino]thieno[2,3-d]pyrimidine-6-car boxylic acid (150 mg, 0.4083 mmol, 81% yield) as a sticky solid. ¾ NMR (400 MHz, DMSO-d6) d 10.01 (brs, 1H), 8.24 (s, 1H), 7.06-7.11 (m, 1H), 3.48 (t, J = 6.3 Hz, 2H), 2.00-2.03 (m, 3H), 1.71-1.89 (m, 5H), 1.21-1.32 (m, 2H), 0.99-1.08 (m, 2H), 0.62-0.70 (m, 2H). MS (ESI) [M+H] 368.0 (ACN: MEOAc).

Step 7

To a stirred solution of 5-cyclopropyl-4-[(4,4- difluorocyclohexyl)methylamino]thieno[2,3-d]pyrimidine-6-car boxylic acid (100.0 mg, 0.2700 mmol) in THF (5 mL) were added HOBT (73.49 mg, 0.5400 mmol), EDC.HC1 (103.97 mg, 0.5400 mmol), N,N-diisopropylethamine (0.14 mL, 0.8200 mmol) and l-(2- methoxy-4-pyridyl)-N-methyl-methanamine (49.71 mg, 0.3300 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred 16h. After this time, the reaction was quenched with sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude compound was purified by Prep HPLC and fraction were concentrated under reduced pressure to return 5- cyclopropyl-4-[(4,4-difluorocyclohexyl)methylamino]-N-[(2-me thoxy-4-pyridyl)methyl]- N-methyl-thieno[2,3-d]pyrimidine-6-carboxamide (20 mg, 0.0397mmol, 15% yield) as off-white solid. DMSO 100c: 1H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1H), 8.15 (d, J =

5.3 Hz, 1H), 6.90-6.93 (m, 2H), 6.70 (s, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.56 (t, J = 6.3 Hz, 2H), 2.99 (s, 3H), 2.20-2.32 (m, 2H), 2.03-2.06 (m, 4H), 1.77-1.87 (m, 2H), 1.25-1.43 (m, 2H), 1.02-1.04 (m, 2H), 0.72-0.76 (m, 2H). MS (ESI) [M+H] 502.2 (ACN:HOOH).

The following is an example of an analog prepared according to Scheme 5:

4-(cyclohexylmethylamino)-5-cyclopropyl-N-methyl-N-(4-pyridy lmethyl)thieno[2,3- d]pyrimidine-6-carboxamide (compound 62)

Example 6:

Scheme 6 shows a synthetic process for making embodiments of formula (I).

Scheme 6

Step 1

To a stirred solution of ethyl 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (500 mg, 1.95 mmol) in THF (15 mL), was added NaH (93.49 mg, 3.9 mmol) at 0° C. After stirring for 15 min, cyclohexylmethanol (0.37 mL, 2.92 mmol) was added drop wise to the reaction mixture and stirred at ambient temperature for 16 h. After this time, the reaction mixture was quenched with ice-cold water (5 mL) and organic part was extracted with ethyl acetate (2 x 25ml). The organic layer was dried over anhydrous

Na ₂ SC> ₄ , filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (50% EtOAc / Hexane) to afford 4- (cyclohexylmethoxy)-5-methyl-thieno[2,3-d]pyrimidine-6-carbo xylic acid (200 mg, 0.65 mmol, 34% yield). MS (ESI) [M-H] 305.0.

Step 2

To a stirred solution of 4-(cyclohexylmethoxy)-5-methyl-thieno[2,3-d]pyrimidine- 6-carboxylic acid (125 mg, 0.41 mmol) and l-(2-methoxy-4-pyridyl)-/V-methyl- methanamine (93 mg, 0.61 mmol) in DMF (2 mL) were added EDC.HC1 (156 mg, 0.82 mmol), HOBT (110 mg, 0.82 mmol), and N,N-diisopropylethylamine (0.21 mL, 1.22 mmol) at 0° C under an atmosphere of nitrogen. The reaction mixture was then stirred at room temperature for 16h. After this time, the reaction mixture quenched with water (20 mL) and organic part was extracted with ethyl acetate (2 x 50 mL). The organic part washed with water (2 x 15 mL) and brine (20 mL). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product, which was purified by preparative HPLC to yield 4-(cyclohexylmethoxy)-N-[(2-methoxy- 4-pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]pyrimidine-6-car boxamide (85 mg, 0.19 mmol, 47% yield). MS (ESI) [M+H] ⁺ 441.4.

The following are examples of analogs prepared according to Scheme 6:

4-(cyclohexylmethoxy)-5-ethyl-N-[(2-methoxy-4-pyridyl)methyl ]-N-methyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 5): 1H NMR (400 MHz, DMSO- d6) d 8.65 (s, 1H), 8.17-8.11 (m, 1H), 6.89-6.83 (m, 1H), 6.70-6.62 (m, 1H), 4.65- 4.60 (m, 2H), 4.34 (d, J= 5.7 Hz, 2H), 3.83 (s, 3H), 2.92 (s, 3H), 2.85 (d, J= 7.7 Hz, 2H), 1.89-1.58 (m, 6H), 1.30-1.07 (m, 7H), 0.85-0.78 (m, 1H). MS (ESI) [M+H] ⁺ : 455.3 (ACN: MLOAc).

4-[(4,4-difluorocyclohexyl)methoxy]-N,5-dimethyl-N-(4-quinol ylmethyl)thieno[2,3- d]pyrimidine-6-carboxamide (compound 38): 1H NMR (400 MHz, DMSO-d6) d 8.94 (d, J = 4.4 Hz, 1H), 8.68 (s, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 7.81 (s,lH), 7.69 (s, 1H), 7.44 (s, 1H), 5.24 (s, 2H), 4.40 (d, J= 6.0 Hz, 2H), 3.08-2.95 (m, 4H), 2.45 (s, 3H), 2.08-2.03 (m, 2H), 1.91-1.77 (m, 4H), 1.40 (q, J= 12.0 Hz, 2H). MS (ESI) [M+H] ⁺ : 497.2 (ACN: MLOAc).

- N,5-dimethyl-N-(4-quinolylmethyl)-4-(tetrahydropyran-3-ylmet hylamino)thieno[2,3- d]pyrimidine-6-carboxamide (compound 37): 1H NMR (400 MHz, DMSO-d6) d 8.93 (d, J= 4.4 Hz, 1H), 8.33 (s, 1H), 8.19-8.14 (m, 1H), 8.08 (d, J= 8.4 Hz, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.42 (s, 1H), 6.86 (d, J = 6.2 Hz, 1H), 5.21 (s, 2H), 3.78 (dd, J = 3.7, 11.1 Hz, 1H), 3.74-3.66 (m, 1H), 3.39 (t, J= 6.6 Hz, 2H), 3.35-3.34 (m, 1H), 3.20-3.10 (m, 1H), 2.96 (s, 3H), 1.96 (s, 1H), 1.83-1.74 (m, 1H), 1.63-1.55 (m, 1H), 1.48-1.37 (m, 1H), 1.30-1.22 (m, 1H). MS (ESI) [M+H] ⁺ : 462.5 (ACN:

MLOAc).

5-ethyl -N-[(2-methoxy-4-pyridyl)methyl]-N-methyl-4-(tetrahydropyran -3- ylmethoxy)thieno[2,3-d]pyrimidine-6-carboxamide (compound 35): 1H NMR (400 MHz, DMSO-d6) d 8.69 (s, 1H), 8.17 (s, 1H), 6.92-6.87 (m, 1H), 6.72-6.67 (m,

1H), 4.69-4.64 (m, 2H), 4.49-4.34 (m, 2H), 3.97-3.99 (m, 1H), 3.85 (s, 3H), 3.81- 3.73 (m, 1H), 3.38-3.33 (m, 2H), 2.95 (s, 3H), 2.90-2.83 (m, 2H), 2.13-2.07 (m, 1H), 1.92-1.83 (m, 1H), 1.69-1.41 (m, 3H), 1.19 (t, 7= 7.3 Hz, 3H). MS (ESI)

[M+H] ⁺ : 456.6 (ACN: NH ₄ OAc).

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(tetrahydropy ran-3- ylmethoxy)thieno[2,3-d]pyrimidine-6-carboxamide (compound 34): 1H NMR (400 MHz, DMSO-d6) d 8.67 (s, 1H), 8.16 (s, 1H), 6.98-6.54 (m, 2H), 4.69-4.64 (m, 2H), 4.56 (d, J= 7.2 Hz, 1H), 4.43-4.36 (m, 2H), 3.95-3.91 (m, 1H), 3.85 (s, 3H), 3.80-3.71 (m, 1H), 3.42-3.37 (m, 1H), 2.95 (s, 3H), 2.50-2.44 (m, 3H), 2.13-2.05 (m, 1H), 1.91-1.83 (m, 1H), 1.67-1.44 (m, 2H), 1.42 (t, J= 7.0 Hz, 1H). MS (ESI) [M+H] ⁺ : 443.0 (ACN: NH ₄ OAc).

4-[(4,4-difluorocyclohexyl)methoxy]-N,5-dimethyl-N-(5-quinol ylmethyl)thieno[2,3- d]pyrimidine-6-carboxamide (compound 33): H NMR (400 MHz, DMSO-d6) d 8.96 (s, 1H), 8.69-8.62 (m, 2H), 8.03 (s, 1H), 7.81 (t, J= 7.8 Hz, 1H), 7.66-7.61 (m,

2H), 5.21 (s, 2H), 4.39 (d, J= 6.1 Hz, 2H), 3.03-2.98 (m, 2H), 2.84 (s, 3H), 2.33- 2.32 (m, 3H), 2.06-2.01 (m, 2H), 1.90-1.84 (m, 3H), 1.42-1.34 (m, 2H). MS (ESI) [M+H] ⁺ : 496.8 (ACN: NH ₄ OAc).

5-ethyl -N-[(2-methoxy-4-pyridyl)methyl]-N-methyl-4-(3, 3,3- trifluoropropoxy)thieno[2,3-d]pyrimidine-6-carboxamide (compound 93)

4-[(4,4-difluorocyclohexyl)methoxy]-N,5-dimethyl-N-(4-pyridy lmethyl)thieno[2,3- d]pyrimidine-6-carboxamide (compound 67)

4-[(4,4-difluorocyclohexyl)methoxy]-N-[(2-methoxy-4-pyridyl) methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 19): 1H NMR (400 MHz, DMSO-d6) d 8.67 (s, 1H), 8.16 (s, 1H), 6.99-6.52 (m, 2H), 4.69-4.64 (m, 2H), 4.42 (d, J= 6.0 Hz, 2H), 3.85 (s, 3H), 2.95 (s, 3H), 2.47 (s, 3H), 2.09-2.02 (m, 3H), 1.86-1.94 (m, 4H), 1.49-1.35 (m, 2H). MS (ESI) [M+H] ⁺ : 477.2 (ACN: NH ₄ OAc). 4-(cyclohexylmethoxy)-N,5-dimethyl-N-(4-pyridylmethyl)thieno [2,3-d]pyrimidine-6- carboxamide (compound 13): lH NMR (400 MHz, DMSO-d6) d 8.57 (d, J = 5.0 Hz, 2H), 8.33 (s, 1H), 7.27 (s, 2H), 6.85 (t, J = 5.6 Hz, 1H), 4.68 (s, 2H), 3.38 (t, J= 6.2 Hz, 2H), 2.96 (s, 3H), 2.52 (s, 3H), 1.74-1.61 (m, 6H), 1.25-1.13 (m, 3H), 1.01-0.91 (m, 2H). MS (ESI) [M+H] ⁺ : 410.1 (ACN: NH ₄ OAc).

4-(cyclohexylmethoxy)-N-[(2-methoxy-4-pyridyl)methyl]-N,5-di methyl-thieno[2,3- d]pyrimidine-6-carboxamide (compound 12): lH NMR (400 MHz, DMSO-d6) d 8.66 (s, 1H), 8.16 (d, J= 5.0 Hz, 1H), 6.99-6.55 (m, 2H), 4.65 (s, 2H), 4.34 (d, J= 5.8 Hz, 2H), 3.85 (s, 3H), 2.96 (s, 3H), 2.48 (s, 3H), 1.86-1.79 (m, 3H), 1.77-1.63 (m, 3H), 1.33-1.05 (m, 5H). MS (ESI) [M+H] ⁺ : 441.4 (ACN: NH ₄ OAc).

4-[(4,4-difluorocyclohexyl)methoxy]-5-ethyl-N-[(2-methoxy-4- pyridyl)methyl]-N- methyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 11): 1H NMR (400 MHz, DMSO-d6) d 8.69 (s, 1H), 8.17 (s, 1H), 6.89 (s, 1H), 6.69 (s, 1H), 4.63-4.68 (m, 2H),

4.45 (d, J= 5.9 Hz, 2H), 3.85 (s, 3H), 2.95 (s, 3H), 2.87 (d, J= 7.6 Hz, 2H), 2.03- 2.10 (m, 3H), 1.77-1.94 (m, 4H), 1.38-1.49 (m, 2H), 1.19 (t, J= 7.3 Hz, 3H). MS (ESI) [M+H] ⁺ : 491.0 (ACN: MLOAc).

Example 7: Scheme 7 shows a synthetic process for making embodiments of formula (I).

Scheme 7

Step 1

To a stirred solution of ethyl 4-chloro-5-ethyl-thieno[2,3-d]pyrimidine-6- carboxylate (120 mg, 0.44 mmol) in CH2CI2 (5 mL) was added NEt3 (0.19 mL, 1.33 mmol) at 0° C. After stirring at this temperature for 5 minutes, A-methyl-l- tetrahydrofuran-3-yl-methanamine (56 mg, 0.49 mmol) dissolved in 1 ml of CH2CI2 was added, and the reaction stirred for 16 h at 25° C. After the starting material was

consumed, the reaction was quenched with crushed ice, diluted with CH2CI2 (200 mL), and the mixture washed with water (3x25 mL). The organic layer was dried over

anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product carried forward without additional purification. MS (ESI) [M+H] ⁺ 349.7

Step 2

To a stirred solution of ethyl 5-ethyl-4-[methyl(tetrahydrofuran-3- ylmethyl)amino]thieno[2,3-d]pyrimidine-6-carboxylate (239 mg, 0.68 mmol) in a mixture of THF (2.9 mL) and Water (1 mL) was added LIOH.H20 (86.1mg, 2.05 mmol) at 0° C. The reaction mixture was then stirred at ambient temperature for 16h. After SM was consumed, the reaction mixture was concentrated in vacuo , and diluted with cold water (20 mL). The solution was acidified with an aqueous solution of citric acid (pH= 3 to 4), followed by extraction with 10% MeOH/DCM (3 x 50 mL). The volatiles were removed under vacuum, and the crude product azeotroped with toluene to afford crude 5-ethyl-4- [methyl(tetrahydrofuran-3-ylmethyl)amino]thieno[2,3-d]pyrimi dine-6-carboxylic acid (105 mg, 0.33 mmol, 48% yield), which was directly used in next step without further purification. MS (ESI) [M-H]- 319.9.

Step 3

To a stirred solution of 5-ethyl-4-[methyl(tetrahydrofuran-3- ylmethyl)amino]thieno[2,3-d]pyrimidine-6-carboxylic acid (103, 0.32 mmol) and l-(2- methoxy-4-pyridyl)-N-methyl-methanamine hydrochloride (91 mg, 0.48 mmol) in

CH2CI2 (5 mL) were added EDC.HC1 (122 mg, 0.64 mmol), HOBt (87 mg, 0.64 mmol), and N,N-diisopropylethylamine (0.17 mL, 0.96 mmol) at 0° C. The reaction was allowed to warm to ambient temperature, and stirred for 12h. After this point, the reaction mixture quenched with water (50 mL), and organic part was extracted with ethyl acetate (2 x 70 mL). The organic phase was washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by prep HPLC to afford 5-ethyl-N-[(2-methoxy-4-pyridyl)methyl]-N-methyl-4- [methyl(tetrahydrofuran-3-ylmethyl)amino]thieno[2,3-d]pyrimi dine-6-carboxamide (48 mg, 0.106 mmol, 33% yield). 1H NMR (400 MHz, DMSO-d6) d 8.48 (s, 1H), 8.16 (d, J =

5.3 Hz, 1H), 6.88 (d, J = 5.1 Hz, 1H), 4.66 (s, 2H), 3.89 (s, 3H), 3.68-3.75 (m, 2H), 3.56- 3.67 (m, 1H), 3.53 (t, J = 7.4 Hz, 2H), 3.29-3.38 (m, 1H), 2.98-3.08 (m, 6H), 2.89-2.94 (m, 2H), 2.65-2.73 (m, 1H), 1.92-2.00 (m, 1H), 1.45-1.55 (m, 1H), 1.12 (t, J = 7.4 Hz,

3H). MS (ESI) [M+H] ⁺ 455.8.

The following are examples of analogs prepared according to Scheme 7:

5-ethyl -4-[(l -hydroxy cyclopropyl)methylamino]-N-[(2-methoxy-4-pyridyl)methyl]- N-methyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 145)

5-ethyl -N-[(2-methoxy-4-pyridyl)methyl]-4-[(2-methoxy-4-pyridyl)met hylamino]-N- methyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 92)

5-ethyl -N-[(2-methoxy-4-pyridyl)methyl]-N-methyl-4-(3- pyridylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 31): 1H NMR (400 MHz, DMSO-d6) d 8.66 -8.60 (m, 1H), 8.50-8.43 (m, 1H), 8.35 (s, 1H), 8.16 (d, J= 5.2 Hz, 1H), 7.83 (d, 7= 8.1 Hz, 1H), 7.50 (t, J= 5.9 Hz, 1H), 6.87 (s, 1H), 7.43-7.35 (m, 1H), 6.66 (s, 1H), 4.81 (d, J = 5.7 Hz, 2H), 4.64 (s, 2H), 3.85 (s, 3H), 3.00-2.92 (m, 5H), 1.16 (t, J= 7.4 Hz, 3H). MS (ESI) [M+H] ⁺ : 448.8 (ACN: MEOAc).

5-ethyl -N-[(2-methoxy-4-pyridyl)methyl]-N-methyl-4-(2- pyridylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 30): 1H NMR (400 MHz, DMSO-d6) d 8.57-8.50 (m, 1H), 8.34 (s, 1H), 8.17 (d, J= 5.3 Hz, 1H), 7.79-7.70 (m, 1H), 7.58 (t, J= 5.3 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.29 - 7.25 (m, 1H), 6.89 (s, 1H), 6.68 (s, 1H), 4.87 (d, J= 5.2 Hz, 2H), 4.66 (s, 2H), 3.86 (s, 3H), 3.04-2.96 (m, 5H), 1.24 (t, J= 7.4 Hz, 3H). MS (ESI) [M+H] ⁺ : 448.8 (ACN: MEOAc).

5-ethyl -N-[(2-methoxy-4-pyridyl)methyl]-N-methyl-4-(3, 3,3- trifluoropropylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 29): 1H NMR (400 MHz, DMSO-d6) d 8.42 (s, 1H), 8.17 (d, J= 5.3 Hz, 1H), 7.00 (s, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 4.63 (s, 2H), 3.86-3.81 (m, 5H), 2.90-2.87 (m, 2H), 2.70- 2.60 (m, 2H), 1.13 (t, J= 7.4 Hz, 3H). MS (ESI) [M+H] ⁺ : 453.8 (ACN: MEOAc).

4-((bicyclo[2.2.1]hept-5-en-2-ylmethyl)amino)-5-ethyl-N-m ethyl-N-(pyridin-4- ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 64)

5-ethyl -N-[(2-methoxy-4-pyridyl)methyl]-N-methyl-4-(4- pyridylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 60) 4-(l-adamantylmethylamino)-5-ethyl-N-[(2-methoxy-4-pyridyl)m ethyl]-N-methyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 58)

4-[[(lS,4S)-5-bicyclo[2.2.1]hept-2-enyl]methylamino]-5-ethyl -N-methyl-N-(5- quinolylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 2): lH NMR (400 MHz, DMSO-d6) d 8.96 (s, 1H), 8.61-8.56 (m, 1H), 8.34 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.81 (t, J= 7.8 Hz, 1H), 7.61 (s, 2H), 6.67 (s, 1H), 6.21 (dd, J= 2.9, 5.7 Hz, 1H), 6.10-6.03 (m, 1H), 5.20 (s, 2H), 3.27-3.21 (m, 2H), 2.87-2.78 (m, 6H), 2.57-2.54 (m, 2H), 1.86-1.76 (m, 1H), 1.35-1.04 (m, 6H). MS (ESI) [M+H] ⁺ : 484.2 (ACN: MROAc).

Example 8:

Scheme 8 shows a synthetic process for making embodiments of formula (I). Scheme 8

Step 1

To a stirred solution of ethyl 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (150 mg, 0.58 mmol) in THF (5 mL) was added NEt3 (0.25 mL, 1.75 mmol), followed by [l-(difluoromethyl)imidazol-2-yl]methanamine (129 mg, 0.88 mmol) at 0° C. The reaction was warmed to ambient temperature and stirred for 12 h. After this time, the reaction mixture was evaporated to dryness, and purified by silica gel chromatography to afford ethyl 4-[[l-(difluoromethyl)imidazol-2-yl]methylamino]-5-methyl-th ieno[2,3- d]pyrimidine-6-carboxylate (125 mg, 0.34 mmol, 58% yield) as white solid. MS (ESI) [M+H] ⁺ 368.1.

Step 2

To a stirred solution of ethyl 4-[[l-(difluoromethyl)imidazol-2-yl]methylamino]- 5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (125 mg, 0.34 mmol) in THF (5 mL), was added a solution of LiOH (43 mg, 1.02 mmol) in water (2 mL) at ambient

temperature. The reaction was mixture was stirred at same temperature for 12 h. After consumption of the starting material, the reaction was evaporated to dryness, acidified with acetic acid, and the resultant solid filtered, washed with water, and dried to yield 4- [[l-(difluoromethyl)imidazol-2-yl]methylamino]-5-methyl-thie no[2,3-d]pyrimidine-6- carboxylic acid (95 mg, 0.28 mmol, 82% yield). MS (ESI) [M+H] ⁺ 340.2.

Step 3

To a stirred solution of 4-[[l-(difluoromethyl)imidazol-2-yl]methylamino]-5- methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (95 mg, 0.28 mmol) in DMF (2 mL), were added HOBT (76 mg, 0.56 mmol) and EDCI (107.34mg, 0.5600 mmol) at 0 °C. 1- (2-methoxy-4-pyridyl)-A ^f -methyl-methanamine hydrochloride (79 mg, 0.42 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol) were then added at this same temperature. The reaction was allowed to warm to ambient temperature and stirred for 12 h. At this time, the reaction was concentrated under reduced pressure and purified by prep-HPLC to obtain 4-[[l-(difluoromethyl)imidazol-2-yl]methylamino]-N-[(2-metho xy- 4-pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]pyrimidine-6-car boxamide (compound 143) (25 mg, 0.053 mmol, 19% yield). 1H NMR (400 MHz, DMSO-d6) d 2.56 (s, 3H), 2.95 (s, 3H), 3.85 (s, 3H), 4.64 (s, 2H), 4.87 (d, J = 5.3 Hz, 2H), 6.68 (s, 1H), 6.88 (s, 1H), 7.00 (s, 1H), 7.46-7.51 (m, 1H), 7.53 (s, 1H), 7.92-8.23 (m, 2H), 8.36 (s, 1H). MS (ESI)

[M+H] ⁺ 474.0. The following are examples of analogs prepared according to Scheme 8:

4-[(2,5-dimethylcy cl ohex-3-en-l -yl)methylamino]-N, 5-dimethyl -N-(4- quinolylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 39)

4-[[(lS,4S)-5-bicyclo[2.2. l]hept-2-enyl]methylamino]-N, 5-dimethyl -N-(3- pyridylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 102)

4-(cyclopropylmethylamino)-N,5-dimethyl-N-(5-quinolylmethyl) thieno[2,3- d]pyrimidine-6-carboxamide (compound 40)

4-(cyclobutylmethylamino)-N,5-dimethyl-N-(5-quinolylmethyl)t hieno[2,3- d]pyrimidine-6-carboxamide (compound 41)

4-(5-bicyclo[2.2.1]hept-2-enylmethylamino)-N-(2,3-dihydro-l, 4-benzodioxin-5- ylmethyl)-N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 103) 4-(l,4-dioxan-2-ylmethylamino)-N, 5-dimethyl -N-(5-quinolylmethyl)thieno[2, 3- d]pyrimidine-6-carboxamide (compound 42)

- N,5-dimethyl-N-(5-quinolylmethyl)-4-(tetrahydrofuran-2-ylmet hylamino)thieno[2,3- d]pyrimidine-6-carboxamide (compound 43)

4-(cy cl ohexylmethylamino)-N, 5-dimethyl -N-(5-quinolylmethyl)thieno[2, 3- d]pyrimidine-6-carboxamide (compound 44)

4-(cy cl ohexylmethylamino)-N, 5-dimethyl -N-(4-pyridylmethyl)thieno[2, 3- d]pyrimidine-6-carboxamide (compound 45)

4-[[(lS,4S)-5-bicyclo[2.2. l]hept-2-enyl]methylamino]-N, 5-dimethyl -N-(quinoxalin-

5-ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 46)

4-(cy cl ohexylmethylamino)-N, 5-dimethyl -N-(pyrimidin-4-ylmethyl)thieno[2, 3- d]pyrimidine-6-carboxamide (compound 104)

N,5-dimethyl-4-[(l-methylcyclohexyl)methylamino]-N-(4-pyridy lmethyl)thieno[2,3- d]pyrimidine-6-carboxamide (compound 105)

4-[[(lS,4S,5R)-5-bicyclo[2.2.1]hept-2-enyl]methylamino]-N,5- dimethyl-N- (quinazolin-4-ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 47) 4-[[(lS,4S)-5-bicyclo[2.2.1]hept-2-enyl]methylamino]-N-ethyl -5-methyl-N-(4- pyridylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 106)

4-[[(lS,4S)-5-bicyclo[2.2.1]hept-2-enyl]methylamino]-N-ethyl -5-methyl-N-(5- quinolylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 107)

4-[[(lS,4S)-5-bicyclo[2.2.1]hept-2-enyl]methylamino]-N-[(2-m ethoxy-4- pyridyl)methyl]-N, 5-dimethyl -thieno[2,3-d]pyrimidine-6-carboxamide (compound 1): 1H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1H), 8.16 (d, J= 5.2 Hz, 1H), 6.92-6.76 (m, 2H), 6.67 (s, 1H), 6.21 (dd, J= 3.1, 5.7 Hz, 1H), 6.08 (dd, J= 2.9, 5.7 Hz, 1H), 4.64 (s, 2H), 3.85 (s, 3H), 3.27-3.21 (m,2H), 2.95 (s, 3H), 2.86-2.76 (m, 3H), 2.53 (s, 3H), 1.87-1.78 (m, 1H), 1.46-1.16 (m, 3H). MS (ESI) [M+H] ⁺ : 450.2 (ACN:

MEOAc).

4-(2-azaspiro[3.5]nonan-2-yl)-N, 5-dimethyl -N-(4-pyridylmethyl)thieno[2, 3- d]pyrimidine-6-carboxamide (compound 108)

4-(5-bicyclo[2.2.1]hept-2-enylmethylamino)-N,5-dimethyl-N-[( 2-methyl-4- pyridyl)methyl]thieno[2,3-d]pyrimidine-6-carboxamide (compound 48)

4-[(3,3-difluorocyclobutyl)methylamino]-N, 5-dimethyl -N-(4- pyridylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 109)

N,5-dimethyl-4-(pyrazin-2-ylmethylamino)-N-(5-quinolylmethyl )thieno[2,3- d]pyrimidine-6-carboxamide (compound 49)

N,5-dimethyl-4-(oxetan-2-ylmethylamino)-N-(4-pyridylmethyl)t hieno[2,3- d]pyrimidine-6-carboxamide (compound 110)

N,5-dimethyl-4-(3-pyridylmethylamino)-N-(5-quinolylmethyl)th ieno[2,3- d]pyrimidine-6-carboxamide (compound 50)

4-[(4,4-difluorocy cl ohexyl)methylamino]-N, 5-dimethyl -N-(4- pyridylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 51)

4-(2-azaspiro[4.5]decan-2-yl)-N,5-dimethyl-N-(4-pyridylmethy l)thieno[2,3- d]pyrimidine-6-carboxamide (compound 111)

4-(2-furylmethylamino)-N, 5-dimethyl -N-(4-pyridylmethyl)thieno[2,3-d]pyrimidine-6- carboxamide (compound 112)

- N,5-dimethyl-N-(4-pyridylmethyl)-4-(tetrahydropyran-4-ylmeth ylamino)thieno[2,3- d]pyrimidine-6-carboxamide (compound 113)

N,5-dimethyl-4-(2-pyridylmethylamino)-N-(5-quinolylmethyl)th ieno[2,3- d]pyrimidine-6-carboxamide (compound 52)

4-[[(l S,4S)-5-bicyclo[2.2. l]hept-2-enyl]methylamino]-N, 5-dimethyl -N-[(l- oxidopyridin-l-ium-4-yl)methyl]thieno[2,3-d]pyrimidine-6-car boxamide (compound 114)

4-(cyclohexylmethylamino)-N-(8-isoquinolylmethyl)-N,5-dimeth yl-thieno[2,3- d]pyrimidine-6-carboxamide (compound 115) 4-(5-bicyclo[2.2.1]hept-2-enylmethylamino)-N,5-dimethyl-N-(p yridazin-4- ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 53)

4-(cy cl ohexylmethylamino)-N-[(2, 6-dimethyl -4-pyridyl)methyl]-N, 5-dimethyl - thieno[2,3-d]pyrimidine-6-carboxamide (compound 3): 1H NMR (400 MHz, DMSO- d6) d 8.33 (s, 1H), 6.93 - 6.82 (m, 3H), 4.59 (s, 2H), 3.38 (t, J= 6.3 Hz, 2H), 2.94 (s, 3H), 2.41 (s, 6H), 1.79-1.57 (m, 7H), 1.26-1.12 (m, 5H), 0.99-0.91 (m, 2H). MS (ESI) [M+H] ⁺ : 437.9 (ACN: NH ₄ OAc).

4-(l-cyclobutylethylamino)-N,5-dimethyl-N-(4-pyridylmethyl)t hieno[2,3- d]pyrimidine-6-carboxamide (compound 116)

4-[(3,3-dimethylcyclobutyl)methylamino]-N,5-dimethyl-N-(4- pyridylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 54)

4-(l-cy cl ohexylethylamino)-N, 5-dimethyl -N-(4-pyridylmethyl)thieno[2, 3- d]pyrimidine-6-carboxamide (compound 55)

- N,5-dimethyl-N-(4-pyridylmethyl)-4-(spiro[3.3]heptan-2-ylmet hylamino)thieno[2,3- d]pyrimidine-6-carboxamide (compound 56)

4-(5-bicyclo[2.2.1]hept-2-enylmethylamino)-N,5-dimethyl-N-(4 - pyridylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 4): 1H NMR (400 MHz, DMSO-d6) d 8.57 (d, J= 4.9 Hz, 2H), 8.34 (s, 1H), 7.27 (brs, 2H), 6.21 (dd, J = 2.9, 5.7 Hz, 1H), 6.11 - 6.05 (m, 2H), 4.69 (s, 2H), 3.24 (s, 2H), 2.96 (s, 3H), 2.54 (s, 3H), 1.88-1.78 (m, 2H), 1.33-1.13 (m, 5H), 0.64 (d, 7= 11.6 Hz, 1H). MS (ESI) [M+H] ⁺ : 420.2 (ACN: NH ₄ OAc).

4-(cyclohexylmethylamino)-N-[(2-cyclopiOpyl-4-pyridyl)methyl ]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 57)

N,5-dimethyl-4-(oxetan-3-ylmethylamino)-N-(4-pyridylmethyl)t hieno[2,3- d]pyrimidine-6-carboxamide (compound 117)

4-(cyclohexylmethylamino)-5-methyl-N-[l-(4-pyridyl)ethyl]thi eno[2,3-d]pyrimidine- 6-carboxamide (compound 118)

4-(cy cl ohexylmethylamino)-N, 5-dimethyl -N-[l-(4-pyridyl)ethyl]thieno[2, 3- d]pyrimidine-6-carboxamide (compound 59)

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(spiro[3.5]no nan-7- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 61)

- N-[(2, 6-dimethyl -4-pyridyl)methyl]-N, 5-dimethyl -4-(spiro[3.5]nonan-7- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 6): 1H MR (400 MHz, DMSO-d6) d 8.33 (s, 1H), 7.04-6.76 (m, 3H), 4.59 (s, 2H), 3.36 (t, J= 6.2 Hz, 2H), 2.94 (s, 3H), 2.41 (s, 6H), 1.85-1.51 (m, 14H), 1.24-1.12 (m, 2H), 1.05-0.91 (m, 2H). MS (ESI) [M+H] ⁺ : 478.2 (ACN: NH ₄ OAc).

4-(cy cl ohexylmethylamino)-N, 5-dimethyl -N-[l -(2-methyl -4-pyridyl)ethyl]thieno[2, 3- d]pyrimidine-6-carboxamide (compound 63)

4-[(4,4-dimethylcyclohexyl)methylamino]-N-[(2-methoxy-4-pyri dyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 7): 1H NMR (400 MHz, DMSO-d6) d 8.33 (s, 1H), 8.16 (d, J= 5.3 Hz, 1H), 6.87-6.80 (m, 2H), 6 JO- 6.64 (m, 1H), 4.63 (s, 2H), 3.85 (s, 3H), 3.42 (t, J= 6.3 Hz, 2H), 2.94 (s, 3H), 2.52 (s, 3H), 1.61-1.53 (m, 3H), 1.36 (d, J= 9.7 Hz, 2H), 1.23-1.05 (m, 4H), 0.87 (s, 6H).

MS (ESI) [M+H] ⁺ : 468.2 (ACN: NH ₄ OAc).

4-(cy cl ohexylmethylamino)-N-[l-(2-methoxy-4-pyridyl)ethyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 65)

4-(cyclohexylmethylamino)-N-[[2-(difluoromethoxy)-4-pyrid yl]methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 125)

4-(cy cl ohexylmethylamino)-N-[(2-ethoxy-4-pyridyl)methyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 69)

4-(cy cl ohexylmethylamino)-N-[(3-fluoro-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3- d]pyrimidine-6-carboxamide (compound 127)

4-[(4,4-difluorocyclohexyl)methylamino]-N-[(3-fluoro-4-pyrid yl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 128)

4-(cy cl ohexylmethylamino)-N, 5-dimethyl -N-[[2-(trifluoromethyl)-4- pyridyl]methyl]thieno[2,3-d]pyrimidine-6-carboxamide (compound 129)

4-[(4,4-difluorocyclohexyl)methylamino]-N-[(3-methoxy-4-p yridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 20): 1H NMR (400 MHz, DMSO-d6) d 8.33-8.38 (m, 2H), 8.24 (d, J= 4.7 Hz, 1H), 7.17 (d, J= 4.7 Hz, 1H), 6.96 (s, 1H), 4.62 (brs, 2H), 3.90 (brs, 3H), 3.45 (t, J= 6.3 Hz, 2H), 2.94 (s, 3H), 2.52 (s, 3H), 1.95-2.07 (m, 2H), 1.68-1.85 (m, 5H), 1.19-1.28 (m, 2H). MS (ESI) [M+H] ⁺ : 476.5 (ACN: NH ₄ OAc).

4-(cy cl ohexylmethylamino)-N-[(2-hydiOxy-4-pyridyl)methyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 131)

[4-[(4,4-difluorocyclohexyl)methylamino]-5-methyl-thieno[2,3 -d]pyrimidin-6-yl]-(7- methoxy-3,4-dihydro-lH-2,6-naphthyridin-2-yl)methanone (compound 133) 4-[(4,4-difluorocy cl ohexyl)methylamino]-N, 5-dimethyl -N-(5- quinolylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 21): 1H NMR (400 MHz, DMSO-d6) d 8.95 (s, 1H), 8.67-8.47 (m, 1H), 8.33 (s, 1H), 8.02 (d, J= 8.5 Hz, 1H), 7.83-7.77 (m, 1H), 7.60 (s, 2H), 6.91-6.85 (m, 1H), 5.19 (s, 2H), 3.43 (t, J =

6.2 Hz, 2H), 2.90-2.81 (m, 3H), 2.45-2.40 (m, 2H), 2.04-1.94 (m, 2H), 1.84-1.66 (m, 5H), 1.28-1.16 (m, 2H). MS (ESI) [M+H] ⁺ : 496.0 (ACN: NH ₄ OAc).

N-(lH-benzimidazol-4-ylmethyl)-4-[(4,4-difluorocyclohexyl)me thylamino]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 73)

4-[(4,4-difluorocyclohexyl)methylamino]-N-(lH-indazol-7-ylme thyl)-N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 135)

4-[(4,4-difluorocy cl ohexyl)methylamino]-N, 5-dimethyl -N-(quinazolin-4- ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 77)

4-[(4,4-difluorocyclohexyl)methylamino]-N-[2-methoxy-l-(2-me thoxy-4- pyridyl)ethyl]-N, 5-dimethyl -thieno[2,3-d]pyrimidine-6-carboxamide (compound 139) N-[(3-chloro-4-pyridyl)methyl]-4-[(4,4-difluorocyclohexyl)me thylamino]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 82)

4-[(4,4-difluorocyclohexyl)methylamino]-5-methyl-N-(4-pyridy lmethyl)thieno[2,3- d]pyrimidine-6-carboxamide (compound 144)

- N-[(2, 6-dimethyl -4-pyridyl)methyl]-N, 5-dimethyl -4-[(l - methylcyclobutyl)methylamino]thieno[2,3-d]pyrimidine-6-carbo xamide (compound 15): 1H NMR (400 MHz, DMSO-d6) d 8.33 (s, 1H), 6.98-6.93 (m, 2H), 6.68 (t, J =

6.3 Hz, 1H), 4.61 (s, 2H), 3.60 (d, J= 6.0 Hz, 2H), 2.95 (s, 3H), 2.55 (s, 3H), 2.43 (s, 6H), 2.05-1.94 (m, 2H), 1.92-1.74 (m, 2H), 1.68-1.57 (m, 2H), 1.15 (s, 3H). MS (ESI) [M+H] ⁺ : 424.4 (ACN: MROAc).

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(3-pyridylmet hylamino)thieno[2,3- d]pyrimidine-6-carboxamide (compound 10): lH MR (400 MHz, DMSO-d6) d 8.61 (s, 1H), 8.43 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 8.16 (d, 7= 5.1 Hz, 1H), 7.78 (d, 7 =

7.7 Hz, 1H), 7.57 (s, 1H), 7.36-7.28 (m, 1H), 6.88 (s, 1H), 6.67 (s, 1H), 4.77 (d, J =

5.7 Hz, 2H), 4.64 (s, 2H), 3.85 (s, 3H), 2.95 (s, 3H), 2.57 (s, 3H). MS (ESI) [M+H] ⁺ :

435.3 (ACN: MROAc).

N-[(2-methoxy-4-pyridyl)methyl]-4-[(2-methoxy-4-pyridyl)meth ylamino]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 18): 1H NMR (400 MHz, DMSO-d6) d 8.30 (s, 1H), 8.16 (d, J= 5.3 Hz, 1H), 8.06 (d, J = 5.2 Hz, 1H), 7.54 (t, J= 5.8 Hz, 1H), 6.97 (d, J= 5.2 Hz, 1H), 6.91-6.86 (m, 1H), 6.74 (s, 1H), 6.71-6.65 (m, 1H), 4.71 (d, J= 5.8 Hz, 2H), 4.65 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 2.96 (s, 3H), 2.59 (s, 3H). MS (ESI) [M+H] ⁺ : 464.8 (ACN: NH ₄ OAc).

- N-[(2, 6-dimethyl -4-pyridyl)methyl]-N,5-dimethyl-4-[[l- (trifluoromethyl)cyclopropyl]methylamino]thieno[2,3-d]pyrimi dine-6-carboxamide (compound 14): 1H NMR (400 MHz, DMSO-d6) VT NMR lOOC d 8.37 (s, 1H), 6.97 (s, 2H), 6.61-6.55 (m, 1H), 4.62 (s, 2H), 3.95 (d, J= 6.0 Hz, 2H), 2.53 (s, 3H), 2.50 (s, 3H), 2.47 (s, 6H), 1.08-0.93 (m, 4H). MS (ESI) [M+H] ⁺ : 464.0 (ACN: MROAc). N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[(l- methylcyclopropyl)methylamino]thieno[2,3-d]pyrimidine-6-carb oxamide (compound 9): 1H NMR (400 MHz, DMSO-d6) d 8.33 (s, 1H), 8.16 (d, J= 5.4 Hz, 1H), 6.90- 6.85 (m, 1H), 6.72-6.65 (m, 2H), 4.64 (s, 2H), 3.85 (s, 3H), 3.50 (d, J= 5.8 Hz, 2H), 2.95 (s, 3H), 2.55 (s, 3H), 1.10 (s, 3H), 0.56(s, 2H), 0.26 (s, 2H). MS (ESI) [M+H] ⁺ : 412.2 (ACN: MROAc).

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(3,3,3- trifluoropropylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 8): 1H NMR (400 MHz, Chloroform-d) d 8.46 (s, 1H), 8.15 (d, J= 5.2 Hz, 1H), 6.79-6.74 (m, 1H), 6.64-6.59 (m, 1H), 5.74 (s, 1H), 4.63 (s, 2H), 3.96-3.87 (m, 5H), 3.00 (s, 3H), 2.59-2.45 (m, 5H). MS (ESI) [M+H] ⁺ : 440.1 (ACN: MROAc).

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(2-pyridylmet hylamino)thieno[2,3- d]pyrimidine-6-carboxamide (compound 17): lH NMR (400 MHz, DMSO-d6) d 8.54-8.47 (m, 1H), 8.29 (s, 1H), 8.14 (d, J= 5.3 Hz, 1H), 7.75-7.66 (m, 1H), 7.62 (d, J= 6.3 Hz, 1H), 7.34 (d, J= 7.9 Hz, 1H), 7.28-7.20 (m, 1H), 6.94-6.61 (m, 2H), 4.81 (d, J = 5.5 Hz, 2H), 4.63 (s, 2H), 3.83 (s, 3H), 2.94 (s, 3H), 2.59 (s, 3H). MS (ESI) [M+H] ⁺ : 435.0 (ACN: MROAc).

4-(cy cl ohexylmethylamino)-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 24): lH NMR (400 MHz, DMSO-d6) d 8.33 (s, 1H), 8.16 (d, J= 5.3 Hz, 1H), 6.85 (t, J = 6.4 Hz, 2H), 6.67 (s, 1H), 4.63 (s, 2H), 3.85 (s, 3H), 3.38 (t, J= 6.2 Hz, 2H), 2.94 (s, 3H), 1.78-1.65 (m, 6H), 1.26-1.12 (m, 3H), 0.99-0.92 (m, 2H). MS (ESI) [M+H] ⁺ : 437.9 (ACN:

NH ₄ OAC).

4-[(4,4-difluorocyclohexyl)methylamino]-N-[(2-methoxy-4-pyri dyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 22): 1H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1H), 8.78 (d, J= 4.9 Hz, 1H), 6.95 (d, J= 5.4 Hz, 1H), 6.87 (s, 1H), 6.66 (s, 1H), 4.63 (brs, 2H), 3.84 (s, 3H), 3.45 (t, J= 5.9 Hz, 2H), 2.94 (s, 3H), 2.52 (s, 3H), 2.03-1.99 (m, 2H), 1.83-1.68 (m, 5H), 1.28-1.19 (m, 2H). MS (ESI) [M+H] ⁺ : 475.8 (ACN: NH ₄ OAc).

4-[(4,4-dimethylcy cl ohexyl)methylamino]-N-[(2, 6-dimethyl -4-pyridyl)methyl]-N, 5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 16): 1H NMR (400 MHz, DMSO-d6) d 8.33 (s, 1H), 6.96-6.90 (m, 1H), 6.88-6.82 (m, 2H), 4.62-4.57 (m, 2H), 3.42 (t, J = 6.4 Hz, 2H), 2.94 (s, 3H), 2.42 (s, 6H), 1.68-1.60 (m, 2H), 1.60- 1.52 (m, 2H), 1.39-1.32 (m, 2H), 1.20-1.09 (m, 6H), 0.87 (s, 6H). MS (ESI) [M+H] ⁺ : 466.3 (ACN: MEOAc).

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[(l- methylcyclobutyl)methylamino]thieno[2,3-d]pyrimidine-6-carbo xamide (compound

68)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[[l-

(trifluoromethyl)cyclobutyl]methylamino]thieno[2,3-d]pyri midine-6-carboxamide (compound 66)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(pyrimidin-4- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 78)

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(2,2,2- trifluoroethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 121) N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(pyrazin-2- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 124)

4-[(l-cyclobutyl-l-methyl-ethyl)amino]-N, 5-dimethyl -N-(4- pyridylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 123)

4-(l,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-N,5-dimethyl-N -(pyridin-4- ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 120)

4-[(l-hydroxycyclopropyl)methylamino]-N-[(2-methoxy-4-pyridy l)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 126)

ethyl 4-[(4,4-difluorocyclohexyl)methylamino]-5-methyl-thieno[2,3- d]pyrimidine-6- carboxylate (compound 137)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(pyrimidin-2- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 122) 4-((bicyclo[2.2.1]hept-5-en-2-ylmethyl)amino)-5-methyl-N-(py ridin-3- ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 119)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(thiazol-4- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 130)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(oxazol-4- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 132)

4-[cy cl ohexylmethyl(methyl)amino]-N-[(2-methoxy-4-pyridyl)methyl]-N , 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 70)

4-[(l-fluorocyclohexyl)methylamino]-N-[(2-methoxy-4-pyridyl) methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 71)

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(tetrahydropy ran-3- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 72)

4-[(l-methoxycyclohexyl)methylamino]-N-[(2-methoxy-4-pyridyl )methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 135)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[2-[[4-(trifl uoromethyl)pyrimidin- 2-yl]amino]ethylamino]thieno[2,3-d]pyrimidine-6-carboxamide (compound 74) 4-[(2,2-dimethyltetrahydropyran-4-yl)methylamino]-N-[(2-meth oxy-4- pyridyl)methyl]-N, 5-dimethyl -thieno[2,3-d]pyrimidine-6-carboxamide (compound 136)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[(3,3,3-trifl uoro-2-hydroxy- propyl)amino]thieno[2,3-d]pyrimidine-6-carboxamide (compound 75)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[[4-

(trifluoromethyl)cyclohexyl]methylamino]thieno[2,3-d]pyri midine-6-carboxamide (compound 76)

4-[(3-fluoro-4-pyridyl)methyl-methyl-amino]-N-[(2-methoxy-4- pyridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 23): 1H NMR (400 MHz, DMSO-d6) d 8.56-8.47 (m, 2H), 8.40-8.34 (m, 1H), 8.16 (d, J= 5.3 Hz, 1H), 7.39 (t, J= 5.7 Hz, 1H), 6.89 (brs, 1H), 6.69 (brs, 1H), 4.79 (s, 2H), 4.66 (s, 2H), 3.84 (s, 3H), 3.06-2.96 (m, 6H), 2.47 (s, 3H). MS (ESI) [M+H] ⁺ : 466.8 (ACN: NH ₄ OAc). N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[(3,3,3-trifl uoro-2-phenyl- propyl)amino]thieno[2,3-d]pyrimidine-6-carboxamide (compound 138)

tert-butyl 3-[[[6-[(2-methoxy-4-pyridyl)methyl-methyl-carbamoyl]-5-meth yl- thieno[2,3-d]pyrimidin-4-yl]amino]methyl]pyrrolidine-l-carbo xylate (compound 79) 4-[(3,3-difluorocyclopentyl)methylamino]-N-[(2-methoxy-4-pyr idyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 80)

4-[[4-(difluoromethyl)phenyl]methylamino]-N-[(2-methoxy-4-py ridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 81)

N-[(2-methoxy-4-pyridyl)methyl]-4-[(2-methoxy-4-pyridyl)meth yl-methyl-amino]- N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 83)

4-(7-methoxy-3, 4-dihydro- 1H-2, 6-naphthyridin-2-yl)-N-[(2-methoxy-4- pyridyl)methyl]-N, 5-dimethyl -thieno[2,3-d]pyrimidine-6-carboxamide (compound 25): 1H NMR (400 MHz, DMSO-d6) d 8.58 (s, 1H), 8.17 (d, 7 = 5.3 Hz, 1H), 8.01 (s, 1H), 6.90 (s, 1H), 6.75 (s, 1H), 6.72-6.67 (m, 1H), 4.69-4.60 (m, 4H), 3.88-3.79 (m, 6H), 3.74 (d, J= 6.6 Hz, 2H), 2.99 (s, 3H), 2.93 (t, J= 6.0 Hz, 2H), 2.47 (s, 3H). MS (ESI) [M+H] ⁺ : 491.0 (ACN: NH ₄ OAc).

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(tetrahydropy ran-2- ylmethylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 140)

N-[(2-methoxy-4-pyridyl)methyl]-4-[(3-methoxy-4-pyridyl)meth yl-methyl -amino]- N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 85)

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[[l-(2,2,2-tr ifluoroethyl)-4- piperidyl]methylamino]thieno[2,3-d]pyrimidine-6-carboxamide (compound 84) N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[[4-(trifluor omethyl)thiazol-2- yl]methylamino]thieno[2,3-d]pyrimidine-6-carboxamide (compound 141)

4-[(3-chloro-4-pyridyl)methyl-methyl-amino]-N-[(2-methoxy-4- pyridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 26): 1H NMR (400 MHz, DMSO-d6) d 8.62 (s, 1H), 8.50-8.43 (m, 2H), 8.16 (d, J= 5.2 Hz, 1H), 7.40 (d, J = 5.0 Hz, 1H), 6.89 (s, 1H), 6.69 (s, 1H), 4.80 (s, 2H), 4.66 (s, 2H), 3.84 (s, 3H), 3.07 (s, 3H), 2.99 (s, 3H), 2.46 (s, 3H). MS (ESI) [M+H] ⁺ : 482.9 (ACN: NH ₄ OAc). 4-[[2-(cyclopentoxy)-3,3,3-trifluoro-propyl]amino]-N-[(2-met hoxy-4- pyridyl)methyl]-N, 5-dimethyl -thieno[2,3-d]pyrimidine-6-carboxamide (compound 142)

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[[l-(2,2,2-tr ifluoroethyl)pyrrolidin-

3-yl]methylamino]thieno[2,3-d]pyrimidine-6-carboxamide (compound 146)

4-[[4-(difluoromethyl)cyclohexyl]methylamino]-N-[(2-methoxy- 4-pyridyl)methyl]- N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (compound 95) Example 9:

Scheme 9 shows a synthetic process for making embodiments of formula (I).

Scheme 9

To a stirred solution of 4-chloro-N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (80 mg, 0.22 mmol) in 1,4-Dioxane (0.80 mL) under argon atmosphere was added N,N-diisopropylethylamine (0.08 mL, 0.44 mmol) at 0 °C. 2-methylmorpholine (0.01 mL, 0.2600 mmol) was then added, and the reaction was warmed to ambient temperature and stirred for 16h. After this time, ice water was added, and the reaction mixture was extracted with CLLCh (20 mL x 2). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure, and the crude product was purified by silica gel chromatography to afford N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(2- methylmorpholin-4-yl)thieno[2,3-d]pyrimidine-6-carboxamide (10.2 mg, 0.023 mmol,

10% yield) (compound 86) ¾ NMR (400 MHz, DMSO-d6) d 8.56 (s, 1H), 8.15 (d, J =

5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 3.84-3.91 (m, 4H), 3.67- 3.74 (m, 4H), 3.10-3.21 (m, 1H), 2.98-3.01 (m, 3H), 2.78-2.88 (m, 1H), 2.43-2.48 (m,

3H), 1.12-1.18 (m, 3H). MS (ESI) [M+H] ⁺ 427.7.

The following are examples of analogs prepared according to Scheme 9:

4-(l,l-dioxo-l,4-thiazinan-4-yl)-N-[(2-methoxy-4-pyridyl)met hyl]-N, 5-dimethyl - thieno[2,3-d]pyrimidine-6-carboxamide (compound 88)

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(8-oxa-3-azab icyclo[3.2.1]octan-3- yl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 89)

4-[(5-fluoro-3-pyridyl)amino]-N-[(2-methoxy-4-pyridyl)methyl ]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 90)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[2-(trifluoro methyl)morpholin-4- yl]thieno[2,3-d]pyrimidine-6-carboxamide (compound 91)

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(2,2,3,3,3- pentafluoropropylamino)thieno[2,3-d]pyrimidine-6-carboxamide (compound 147) N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[(2-methyl-3- pyridyl)oxy]thieno[2,3-d]pyrimidine-6-carboxamide (compound 36): 1H NMR-VT (400 MHz, DMSO-d6) d 8.58 (s, 1H), 8.45-8.39 (m, 1H), 8.17 (d, J= 5.2 Hz, 1H),

7.69 (dd, J= 1.5, 8.2 Hz, 1H), 7.39-7.31 (m, 1H), 6.94-6.87 (m, 1H), 6.70 (s, 1H),

4.69 (s, 2H), 3.89 (s, 3H), 3.04 (s, 3H), 2.63 (s, 3H), 2.39 (s, 3H). MS (ESI) [M+H] ⁺ : 435.8 (ACN: NH ₄ OAc).

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[(l-methyl-3- piperidyl)methylamino]thieno[2,3-d]pyrimidine-6-carboxamide (compound 150) 4-[(5-fluoro-3-pyridyl)oxy]-N-[(2-methoxy-4-pyridyl)methyl]- N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 100)

N-[(2-methoxy-4-pyridyl)methyl]-4-[(6-methoxy-3-pyridyl)oxy] -N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 101)

4-[(5-chloro-3-pyridyl)oxy]-N-[(2-methoxy-4-pyridyl)methyl]- N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 151)

Example 10:

Scheme 10 shows a synthetic process for making embodiments of formula (I).

Scheme 10

To a stirred solution of (5-fluoro-2-pyridyl)methanol (0.03 mL, 0.21 mmol) and CS2CO3 (136 mg, 0.42 mmol) in DMF (2.8 mL) at 0 °C was added a solution of 4-chloro- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]py rimidine-6-carboxamide (80 mg, 0.22 mmol) in DMF (1 ml). The reaction warmed to ambient temperature and stirred for 90 minutes. After completion of the reaction, the reaction was diluted with water, and extracted with ethyl acetate (2 x 15 mL). The organic phase was washed with water (20 mL), followed by saturated NaCl (30 mL). After drying over anhydrous sodium sulfate, the organics were filtered and concentrated to afford a crude product, which was purified by silica gel chromatography (50% EtOAc / Hexane) to yield 4-[(5-fluoro-2- pyridyl)methoxy]-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3- d]pyrimidine-6-carboxamide (8 mg, 0.018 mmol, 8% yield) (compound 97). 1H NMR (400 MHz, DMSO-d6) d 8.66 (s, 1H), 8.51-8.57 (m, 1H), 8.15 (d, J = 5.1 Hz, 1H), 7.61- 7.77 (m, 2H), 6.87 (d, J = 5.3 Hz, 1H), 6.67 (s, 1H), 5.71 (s, 2H), 4.65 (s, 2H), 3.89 (s,

3H), 2.99 (s, 3H), 2.50 (3H, s). MS (ESI) [M+H] ⁺ 453.9.

The following are examples of analogs prepared according to Scheme 10:

4-[(4-chloro-2-pyridyl)methoxy]-N-[(2-methoxy-4-pyridyl)meth yl]-N, 5-dimethyl - thieno[2,3-d]pyrimidine-6-carboxamide (compound 148)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(2-pyridylmet hoxy)thieno[2,3- d]pyrimidine-6-carboxamide (compound 98)

4-[(4-methoxy-2-pyridyl)methoxy]-N-[(2-methoxy-4-pyridyl)met hyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (compound 149)

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(3-pyridylmet hoxy)thieno[2,3- d]pyrimidine-6-carboxamide (compound 99)

Example 11:

Scheme 11 shows a synthetic process for making embodiments of formula (I).

Scheme 11

Step 1

To stirred a solution of 4,6-dichloropyrimidine-5-carbaldehyde (2.0 g, 11.3 mmol) in CH2CI2 (20 mL) were added N,N-diisopropylethylamine (2.36 mL, 13.56 mmol) and ethyl 2-sulfanylacetate (1.0 mL, 9.04 mmol) at -78°C under a nitrogen environment. The reaction was stirred 6 h at 25 °C, while monitoring by TLC (70% ethyl acetate in hexanes). After this time, the reaction mixture was partitioned between CH2CI2 (50ml ml) and water (50 ml), the organic phase set aside, and the aqueous layer extracted with additional CH2CI2 (2 X 20 ml). The combined organic parts were washed with brine solution (50 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to get crude compound, which was purified by silica gel chromatography to afford ethyl 2-(6-chloro-5-formyl-pyrimidin-4-yl)sulfanylacetate (2.4 g, 9.206 mmol,

81% yield) as pale brown liquid. MS (ESI) [M+H] 261.1 (ACN: NH40Ac).

Step 2

To a stirred solution of ethyl 2-(6-chloro-5-formyl-pyrimidin-4-yl)sulfanylacetate (50.0 mg, 0.19 mmol) in THF (2 mL) were added DBU (0.09 mL, 0.58 mmol) and

[(lS,4S)-5-bicyclo[2.2.1]hept-2-enyl]methanamine (28.35 mg, 0.23 mmol) at 0 °C. After 10 minutes, the reaction mixture was diluted with water (10 mL), and the organic part extracted with ethyl acetate (2 x 50 mL). The combined organics were washed with brine (30 mL) and concentrated under reduced pressure to produce crude product, which was purified by silica gel chromatography (40% ethyl acetate in hexanes) to afford ethyl 4- [[(lS,4S)-5-bicyclo[2.2.1]hept-2-enyl]methylamino]thieno[2,3 -d]pyrimidine-6- carboxylate (30 mg, 0.083 mmol, 43% yield). MS (ESI) [M+H] 330.5 (ACN: NH40Ac).

Step 3

To a stirred solution of ethyl 4-[[(lS,4S)-5-bicyclo[2.2.1]hept-2- enyl]methylamino]thieno[2,3-d]pyrimidine-6-carboxylate (20.0 mg, 0.06 mmol) in ethanol (0.50 mL) and THF (0.20 mL) was added the solution of lithium hydroxide monohydrate (7.65 mg, 0.18 mmol) in water (0.20 mL) at room temperature. After 3h, the reaction mixture was concentrated under reduced pressure, diluted with water (1 mL), and neutralized with acetic acid. The precipitated white solid was collected by filtration and dried under reduced pressure to get 4-[[(lS,4S)-5-bicyclo[2.2.1]hept-2- enyl]methylamino]thieno[2,3-d]pyrimidine-6-carboxylic acid (10 mg, 0.03 mmol, 50% yield). MS (ESI) [M+H] 302.2 (ACN: NH40Ac).

Step 4

To a stirred solution of 4-[[(lS,4S)-5-bicyclo[2.2.1]hept-2- enyl]methylamino]thieno[2,3-d]pyrimidine-6-carboxylic acid (100. mg, 0.3300mmol) in DMF (2 mL) were added N-Methyl-l-quinolin-5-ylmethanamine (68.6 mg, 0.40 mmol), EDC.HCL (127.2 mg, 0.66 mmol)), HOBt (89.6 mg, 0.66 mmol) and NEt (0.14 mL, 1.0 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h, at which time it was diluted with water (10 mL), and the organic part extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with cold water (2 x 10 mL) followed by brine solution (20 mL). The organics were dried over sodium sulphate, filtered, and concentrated under reduced pressure to yield crude product, which was purified by silica gel chromatography (5% MeOH in CH2CI2) to afford 4-[[(lS,4S)-5- bicyclo[2.2.1]hept-2-enyl]methylamino]-N-methyl-N-(5-quinoly lmethyl)thieno[2,3- d]pyrimidine-6-carboxamide (60 mg, 0.13 mmol, 40% yield). MS (ESI) [M+H] 302.2 (ACN: NH ₄ OAC).

The following is an example of an analog prepared according to Scheme 11 :

4-((((l S,4S)-bicyclo[2.2. l]hept-5-en-2-yl)methyl)amino)-N-methyl-N-(quinolin-

5-ylmethyl)thieno[2,3-d]pyrimidine-6-carboxamide (compound 152)

Example 12:

Scheme 12 shows a synthetic process for making embodiments of formula (I).

Scheme 12

Step 1

To a stirred solution of (4,4-difluorocyclohexyl)methanamine (1715 mg, 11.49 mmol) in THF (40 mL) were added N,N-diisopropylethylamine (2.0 mL, 11.49 mmol) and 4,6-dichloropyrimidine-5-carbonitrile (2.0 g, 11.49 mmol) at 0 °C. After 2h, the reaction mixture was quenched with water (10 mL) and organic parts were extracted with ethyl acetate (2 x 15 mL). The organics were concentrated under reduced pressure, and the crude material was purified by silica gel chromatography to afford 4-chloro-6-[(4,4- difluorocyclohexyl)methylamino]pyrimidine-5-carbonitrile (1000 mg, 3.49 mmol, 30% yield). MS (ESI) [M+H] 287.3 (ACN: MLOAc).

Step 2

To a stirred solution of 4-chloro-6-[(4,4- difluorocyclohexyl)methylamino]pyrimidine-5-carbonitrile (950 mg, 3.31 mmol) in THF (23.8 mL) was added Et3 (0.70 mL, 4.97 mmol) and ethyl 2-sulfanylacetate (0.47 mL, 4.31 mmol) drop-wise, and the reaction sealed. The reaction was heated to 80 °C for 16h, after which time the reaction was quenched with cold water and extracted in EtOAc (20 mL). The organic phase was washed with water (20 mL x 2), followed by brine (10 mL). The organics were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was purified by silica gel chromatography (silica 230-400 mesh) to afford ethyl 2-[5-cyano-6-[(4,4-difluorocyclohexyl)methylamino]pyrimidin- 4- yljsulfanylacetate (356 mg, 0.95 mmol, 29% yield)

Step 3

To a stirred solution of methyl 2-[5-cyano-6-[(4,4- difluorocyclohexyl)methylamino]pyrimidin-4-yl]sulfanylacetat e (5000 mg, 14.03 mmol) in THF (200 mL) was added sodium ethoxide (21% w/w in ethanol, 1.1 mL, 14.03 mmol) at ambient temperature under an argon atmosphere. The mixture was then refluxed for 20 min, after which time the reaction the reaction mixture was quenched with cold water and extracted in EtOAc (20 mL). The organic phase was washed with water (20 mL x 2), followed by brine (10 mL) solution. The organics were then separated, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude product was then purified by silica gel chromatography (silica 230-400 mesh) column chromatography to yield ethyl 5-amino-4-[(4,4-difluorocyclohexyl)methylamino]thieno[2,3-d] pyrimidine- 6-carboxylate (3500 mg, 9.45 mmol, 67% yield). MS (ESI) [M+H] 370.8 (ACN:

NH ₄ OAC).

Step 4

To a stirred solution of ethyl 5-amino-4-[(4,4- difluorocyclohexyl)methylamino]thieno[2,3-d]pyrimidine-6-car boxylate (500 mg, 1.35 mmol) in ethanol (4.0 mL) and THF (1.6 mL) was added the solution of lithium hydroxide monohydrate (113 mg, 2.70 mmol) in water (1.6 mL) at room temperature. After 3h, the reaction mixture was concentrated under reduced pressure, diluted with water (5 mL), and neutralized with acetic acid. The precipitated white solid was collected by filtration and dried under reduced pressure to yield 5-amino-4-[(4,4- difluorocyclohexyl)methylamino]thieno[2,3-d]pyrimidine-6-car boxylic acid (300 mg,

0.88 mmol, 65% yield).

Step 5

To a stirred solution of l-(2-methoxy-4-pyridyl)-N-methyl-methanamine (66.68 mg, 0.44 mmol) and 5-amino-4-[(4,4-difluorocyclohexyl)methylamino]thieno[2,3- d]pyrimidine-6-carboxylic acid (100 mg, 0.29 mmol) in DMF (1.5 mL) were added HATU (166.6 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.08 mL, 0.58 mmol) at 0 °C. The reaction was then warmed to ambient temperature, and stirred for 16h. After this time, the reaction mixture was quenched with water (5 mL), and the organic parts extracted with ethyl acetate (2 x 10 mL) and concentrated under reduced pressure. The crude product was purified by prep HPLC to get afford 5-amino-4-[(4,4- difluorocyclohexyl)methylamino]-N-[(2-methoxy-4-pyridyl)meth yl]-N-methyl- thieno[2,3-d]pyrimidine-6-carboxamide (22 mg, 0.045 mmol, 15% yield). ¾NMR (400 MHz, DMSO-i&) d 8.33 (s, 1H), 8.14 (d, J= 5.3 Hz, 1H), 7.36 (s, 1H), 6.88 (d, J= 5.2 Hz, 1H), 6.66 (s, 1H), 6.58 (s, 2H), 4.68 (s, 2H), 3.84 (s, 3H), 3.45 (t, J= 6.2 Hz, 2H), 3.08 (s, 3H), 1.99-2.02 (m, 2H), 1.82 (s, 5H), 1.21-1.24 (m, 2H). MS (ESI) [M+H] 370.8 (ACN: NH40Ac).

The following is an example of an analog prepared according to Scheme 12: 5-amino-4-(((4,4-difluorocyclohexyl)methyl)amino)-N-((2-meth oxypyridin-4- yl)methyl)-N-methylthieno[2,3-d]pyrimidine-6-carboxamide (compound 153)

Example 13:

Scheme 13 shows a synthetic process for making embodiments of formula (I).

Scheme 13

Step 1

To a stirred solution of ethyl 2-cyanoacetate (23.5 mL, 221 mmol) and ethyl 3- oxobutanoate (28.2 mL, 221 mmol) in ethanol (250 mL) was added sulfur powder (7.07 g, 221 mmol), followed by dropwise addition of diethylamine (22.86 mL, 221 mmol).

The reaction was then stirred for 16h at ambient temperature. After this time, the solvent was removed under reduced pressure, and the crude residue slurried with ethyl acetate (240 ml). The organic phase was washed with water (60 mL x 2), followed by saturated NaCl solution (80 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to afford a crude material, which was purified by silica gel chromatography to yield diethyl 5-amino-3-methyl-thiophene-2,4-dicarboxylate (35.0 g, 136.02 mmol, 62% yield). ¾ NMR (400 MHz, DMSO-^e): d 7.91 (br s, 2H), 4.13-4.24 (m, 4H), 2.59 (s, 3H), 1.18-1.32 (m, 6H). MS (ESI+) [M-H] : 256.0 (ACN: NH ₄ OAC).

Step 2

Diethyl 5 -amino-3 -methyl-thiophene-2, 4-dicarboxylate (10.0 g, 38.9 mmol) was added to a solution of formamide (50.0 mL, 1255.6 mmol) and acetic acid (0.50 mL, 38.9 mmol), which was subsequently heated at 160 °C for 12 h. After the reaction was deemed complete, the reaction was quenched with ice water, and the precipitated solid was collected by filtration. After washing with water, the solid product was dried under reduced pressure to afford ethyl 4-hydroxy-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (7.97 g, 33.46 mmol, 86% yield). ¾ NMR (400 MHz, DMSO-7 ₆ ) d 12.52 (s, 1H), 8.20 (s, 1H), 4.26-4.32 (q, J= 7.1 Hz, 2H), 2.80 (s, 3H), 1.28-1.31 (t, 7= 7.1 Hz,

3H). MS (ESI) [M+H] ⁺ : 239.2 (ACN: MEOAc).

Step 3

To a stirred solution of ethyl 4-hydroxy-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (30.0 g, 125.9 mmol) in POCh (35.31 mL, 377.7 mmol) was added PCb (3.78 g, 63 mmol) at ambient temperature. The reaction was then heated to 110 °C for 12 h. After this time, the reaction was quenched with cold water (100 mL) and then neutralized with saturated sodium bicarbonate solution (50 mL). The crude reaction mixture was extracted with ethyl acetate (2 x 250 mL), followed by brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (10% ethyl acetate/hexane) to afford ethyl 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (27.0 g, 105.2 mmol, 84% yield) as a yellow solid. ¾ NMR (400 MHz, DMSO-7 ₆ ) d 9.03 (s, 1H), 4.36-4.41 (q, J= 7.1 Hz, 2H), 2.98 (s, 3H), 1.32-1.36 (t, 7= 7.1 Hz, 3H). MS (ESI) [M+H] ⁺ : 257.0 (ACN:NH ₄ OAc).

Example 14:

Scheme 14 shows a synthetic process for making embodiments of formula (I).

Scheme 14

Step 1

To a stirred solution of methyl 4-hydroxy-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (26.0 g, 116mmol) in a mixture of THF (260 mL) and Water (130 mL) at 0 °C was added LiOH monohydrate (14.6 g, 347.8 mmol). The reaction mixture was stirred at ambient temperature for 16h. After the reaction was complete, the reaction was concentrated under vacuum, diluted with water (30 mL), and acidified with IN HC1. The heterogeneous mixture was extracted with EtOAc (2 x 300 ml), and the combined organic extracts concentrated under reduced pressure to yield 4-hydroxy-5-methyl-thieno[2,3- d]pyrimidine-6-carboxylic acid (19.5 g, 92.7 mmol, 80% yield) as off white solid. ¾ NMR (400 MHz, DMSO-^e) d 12.59 (br, 1H), 8.18 (s, 1H), 2.80 (s, 3H). MS (ESI)

[M+H] ⁺ : 211.2 (ACN: HCOOH).

Step 2

To a stirred solution of 4-hydroxy-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (5.0 g, 23.79 mmol) and l-(2-methoxypyridin-4-yl)-N-methylmethanamine (2905.9 mg, 23.8 mmol) in DMF (54 mL) were added N,N-diisopropylethylamine (10.3 mL, 59.5 mmol), EDC-HC1 (5.45 g, 28.5 mmol), and HOBt (3.85 g, 28.5 mmol) at 0° C under an atmosphere of N2. The reaction was warmed to ambient temperature and let stir for 16h. After this time, the reaction mixture was quenched with cold water and extracted with CH2CI2 (500 mL x 4). The combined organic phase was washed with saturated NaCl solution (200 mL), followed by drying over anhydrous sodium sulfate. The organic phase was filtered and solvent removed to afford the crude product, which was purified by column chromatography (Combi-flash 230-400 silica gel, EtOAc / CH2CI2) to produce 4- hydroxy-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3-d]pyrimidine-6- carboxamide (4.2g, 12.2 mmol, 51% yield). 1H NMR (400 MHz, DMSO-d6) d 12.56 (br, 1H), 8.13-8.15 (m, 2H), 6.86 (s, 1H), 6.66 (s, 1H), 4.62 (s, 2H), 3.84 (s, 3H), 2.94 (s, 3H), 2.44 (s, 3H). MS (ESI) [M+H] ⁺ : 345.3 (ACN: HCOOH).

Step 3

To a stirred solution of 4-hydroxy-N-[(2-methoxy-4-pyridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (1.50 g, 4.36 mmol) in POCb (1.22 mL, 13.1 mmol) was added PCI5 (453 mg, 2.18 mmol) at ambient temperature. The reaction was then heated to 110° C for 4 h. After this time, the reaction was quenched with cold water (10 mL) and neutralized with saturated aqueous sodium bicarbonate solution (10 mL). The crude mixture was extracted with CH2CI2 (2 x 50 mL) and dried over anhydrous sodium sulfate. The organic phase was filtered and concentrated under reduced pressure to afford 4-chloro-N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (l .OOg, 2.76 mmol, 63% yield), which was used without further purification. 1H NMR (400 MHz, DMSO-i/6): d 8.96 (s, 1H), 8.13-8.18 (m, 1H), 6.59-6.95 (m, 2H), 4.70 (s, 2H), 3.86 (s, 3H), 2.94-2.99 (m, 3H), 2.56 (s, 3H). MS (ESI) [M+H] ⁺ : 363.2 (ACN:NH ₄ OAc).

Example 15:

Scheme 15 shows a synthetic process for making embodiments of formula (I).

Scheme 15

Step 1

A stirred solution of 4-chloro-N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (100 mg, 0.28 mmol) and K2CO3 (95 mg, 0.69 mmol) in 1,4-dioxane (3 mL) was degassed for 5 min with N2. After this time, 2-(2,5- dihydrofuran-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (65 mg, 0.33 mmol), P(Cy)3 (15.5 mg, 0.06 mmol), and Pd ₂ dba ₃ (25.2 mg, 0.03 mmol) were added, and the reaction mixture was heated at 110 °C for 16h. After this time, the reaction was passed through a celite bed, and washed with ethyl acetate (2 x 20 mL). The filtrate was washed with water (1 x 20 mL), followed by saturated NaCl (1 x 30 mL). The organics were dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (40% EtOAc in hexane) to afford 4-(2,5-dihydrofuran-3-yl)-N- [(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]pyri midine-6-carboxamide (80 mg, 0.2018 mmol, 73.2% yield) as an off-white solid.

Step 2

A stirred solution of 4-(2,5-dihydrofuran-3-yl)-N-[(2-methoxy-4-pyridyl)methyl]- N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (70 mg, 0.18 mmol) in ethanol (6 mL) and methanol (6 mL) was degassed for 5 min with N2. 20% palladium oxide on carbon (94mg, 0.88 mmol) was added, and the mixture purged with H2 for 1 min. The reaction mixture was stirred for 16 h at RT under a balloon of hydrogen. After completion of the reaction, the reaction was passed through a celite bed, and washed with ethyl acetate (2 x 20mL). The filtrate was concentrated in vacuo , and the crude product purified by prep-HPLC to get afford N-((2-methoxypyridin-4-yl)methyl)-N,5-dimethyl-4- (tetrahydrofuran-3-yl)thieno[2,3-d]pyrimidine-6-carboxamide (45 mg, 0.113 mmol, 64% yield) as a pale yellow solid. ¾ NMR-VT (400 MHz, DMSO-^e, 100 °C) d 8.99 (s, 1H),

8.16 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 5.2 Hz, 1H), 6.68 (s, 1H), 4.66 (s, 2H), 4.39-4.27 (m, 1H), 4.15 (t, J = 7.9 Hz, 1H), 4.01-3.96 (m, 2H), 3.89 (s, 4H), 3.00 (s, 3H), 2.58 (s,

3H), 2.42-2.32 (m, 2H). MS (ESI) [M+H] ⁺ : 427.3 (ACN: HCOOH).

The following are examples of analogs prepared according to Scheme 15:

- N-((2-methoxypyridin-4-yl)methyl)-N, 5-dimethyl -4-(l, 2, 3, 4-tetrahydronaphthalen-2- yl)thieno[2,3-d]pyrimidine-6-carboxamide: 1H NMR (400 MHz, DMSO-d6) d 9.01 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.16-7.09 (m, 4H), 6.88 (s, 1H), 6.67 (s, 1H), 4.66 (s, 2H), 3.97-3.88 (m, 2H), 3.88 (s, 3H), 3.39-3.25 (m, 2H), 3.05-3.02 (m, 2H), 2.55 (s, 3H), 2.22-2.01 (m, 5H). MS (ESI) [M+H] ⁺ : 459.2 (ACN: HCOOH).

4-indan-2-yl-N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-th ieno[2,3- d]pyrimidine-6-carboxamide: 1H MR (400 MHz, DMSO-d6) d 8.94 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 7.27-7.20 (m, 2H), 7.21-7.13 (m, 2H), 6.89 (d, J = 5.2 Hz, 1H), 6.69 (s, 1H), 4.67 (s, 2H), 4.63 (t, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.53-3.34 (m, 4H), 3.02 (s, 3H), 2.64 (s, 3H). MS (ESI) [M+H] ⁺ : 445.2 (ACN: HCOOH).

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-tetrahydropyr an-4-yl-thieno[2,3- d]pyrimidine-6-carboxamide: lH NMR (400 MHz, DMSO-d6) d 9.00 (s, 1H), 8.16 (d, J = 5.1 Hz, 1H), 6.89 (d, J = 5.1 Hz, 1H), 6.68 (s, 1H), 4.66 (s, 2H), 4.00 (dd, J = 4.0, 12.0 Hz, 2H), 3.89 (s, 3H), 3.81 - 3.74 (m, 1H), 3.62 - 3.50 (m, 2H), 2.99 (s, 3H), 2.59 (s, 3H), 2.11 - 1.96 (m, 2H), 1.77 (d, J = 13.3 Hz, 2H). MS (ESI) [M+H] ⁺ : 413.4 (ACN: HCOOH).

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-tetrahydrofur an-2-yl-thieno[2,3- d]pyrimidine-6-carboxamide: 1H NMR (400 MHz, DMSO-d6) d 9.02 (s, 1H), 8.16- 8.15 (d, J = 5.3 Hz, 1H), 6.88-6.87 (d, J = 5.4 Hz, 1H), 6.68 (s, 1H), 5.65-5.62 (m, 1H), 4.66 (s, 2H), 3.98-3.85 (m, 1H), 3.89 (s, 3H), 2.99 (s, 3H), 2.94 (s, 2H), 2.61 (s, 3H), 2.30-2.16 (m, 1H), 2.16-2.00 (m, 2H). MS (ESI) [M+H] ⁺ : 399.0 (ACN: HCOOH). 4-(chroman-3-yl)-N-((2-methoxypyridin-4-yl)methyl)-N,5-dimet hylthieno[2,3- d]pyrimidine-6-carboxamide: ¾ NMR (400 MHz, DMSO-d ₆ ) d 9.06 (s, 1H), 8.17 (s, 1H), 7.21-7.13 (m, 1H), 7.03-6.90 (m, 2H), 6.89-6.52 (m, 2H), 4.80-4.49 (m, 2H), 3.85 (s, 4H), 3.26-3.16 (m, 1H), 3.10-2.85 (m, 6H), 2.64-2.52 (m, 3H), 2.21-2.05 (m, 1H), 2.07-1.88 (m, 1H). MS (ESI) [M+H] ⁺ : 461.1 (ACN: HCOOH).

4-(6-fluoro-l,2,3,4-tetrahydronaphthalen-2-yl)-N-((2-methoxy pyridin-4-yl)methyl)- N,5-dimethylthieno[2,3-d]pyrimidine-6-carboxamide: ¾ NMR (400 MHz, DMSO- de) d 9.06 (s, 1H), 8.17 (s, 1H), 7.21-7.13 (m, 1H), 7.03-6.90 (m, 2H), 6.89-6.52 (m, 2H), 4.80-4.49 (m, 2H), 3.85 (s, 4H), 3.26-3.16 (m, 1H), 3.10-2.85 (m, 6H), 2.64- 2.52 (m, 3H), 2.21-2.05 (m, 1H), 2.07-1.88 (m, 1H). MS (ESI) [M+H] ⁺ : 477.2 (ACN: HCOOH).

N-((2-methoxypyridin-4-yl)methyl)-N, 5-dimethyl -4-(tetrahydro-2H-pyran-4- yl)thieno[2,3-d]pyrimidine-6-carboxamide: 1H NMR (400 MHz, DMSO-76) d 9.00 (s, 1H), 8.16 (d, J = 5.1 Hz, 1H), 6.89 (d, 7= 5.1 Hz, 1H), 6.68 (s, 1H), 4.66 (s, 2H), 4.00 (dd, J = 4.0, 12.0 Hz, 2H), 3.89 (s, 3H), 3.81 - 3.74 (m, 1H), 3.62 - 3.50 (m,

2H), 2.99 (s, 3H), 2.59 (s, 3H), 2.11 - 1.96 (m, 2H), 1.77 (d, 7= 13.3 Hz, 2H). MS (ESI) [M+H] ⁺ : 413.4 (ACN: MROAc).

Example 16:

Scheme 16 shows a synthetic process for making embodiments of formula (I).

Scheme 16

Step 1

To a sealed tube were added 4-chloro-N-[(2-methoxy-4-pyridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (50 mg, 0.14 mmol) in 1,4-dioxane (5 mL), which was then de-gassed with nitrogen for 5 minutes. [6-(trifluoromethyl)-3- pyridyljboronic acid (28.9 mg, 0.1500 mmol), tetrakis(triphenylphosphine)palladium(0) (15.9 mg, 0.01 mmol) and K2CO3 (38 mg, 0.28 mmol) were added, and the tube sealed and heated at 110 °C for 16h. After completion, the reaction was quenched with water (5 mL) and extracted with CH2CI2 (3x10 mL). Combined organic part was washed with 50% brine (2 x lOmL), dried over anhydrous sodium sulfate and concentrated under vacuum to give the crude, which was purified by mass triggered UPLC and dried in lyophilizer to afford N-((2-methoxypyridin-4-yl)methyl)-N,5-dimethyl-4-(6-(trifluo romethyl)pyri din-3- yl)thieno[2,3-d]pyrimidine-6-carboxamide (20 mg, 0.042 mmol, 30.7% yield) as an off- white solid: 1H NMR (400 MHz, DMSO-d6, 100 °C) d 9.20 (s, 1H), 9.01 (s, 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 5.2 Hz, 1H), 8.07 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 5.3 Hz, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 3.88 (s, 3H), 3.00 (s, 3H), 1.91 (s, 3H). MS (ESI) [M+H] ⁺ : 474.2 (ACN: HCOOH).

The following are examples of analogs prepared according to Scheme 16:

4-(5-chloropyridin-3-yl)-N-((2-methoxypyridin-4-yl)methyl)-N ,5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: MS (ESI) [M+H] ⁺ : 440.4 (ACN: HCOOH).

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(6-methyl-3- pyridyl)thieno[2,3-d]pyrimidine-6-carboxamide: MS (ESI) [M+H] ⁺ : 420.3 (ACN: HCOOH).

4-(6-fluoro-3-quinolyl)-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide: MS (ESI) [M+H] ⁺ : 474.4 (ACN:

HCOOH).

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(5-methyl-3- pyridyl)thieno[2,3-d]pyrimidine-6-carboxamide: MS (ESI) [M+H] ⁺ : 420.4 (ACN: HCOOH).

N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-[5-(trifluoro methyl)-3- pyridyl]thieno[2,3-d]pyrimidine-6-carboxamide: MS (ESI) [M+H] ⁺ : 474.4 (ACN: HCOOH).

4-(5-fluoro-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide: MS (ESI) [M+H] ⁺ : 424.4 (ACN:

HCOOH).

4-(6-methoxy-3-pyridyl)-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide: MS (ESI) [M+H] ⁺ : 436.2 (ACN:

HCOOH).

4-(3-fluorophenyl)-N-[(2 -methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3- d]pyrimidine-6-carboxamide: MS (ESI) [M+H] ⁺ : 423.4 (ACN: HCOOH).

4-(4-fluorophenyl)-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3- d]pyrimidine-6-carboxamide: lH NMR (400 MHz, DMSO-d6) d 9.10 (s, 1H),

8.14 (d, J = 5.2 Hz, 1H), 7.60-7.68 (m, 2H), 7.34 (t, J = 8.8 Hz, 2H), 6.86 (d, J = 5.5 Hz, 1H), 6.66 (s, 1H), 4.64 (s, 2H), 3.88 (s, 3H), 2.99 (s, 3H), 1.90 (s, 3H). MS (ESI) [M+H] ⁺ : 423.4 (ACN: HCOOH).

Example 17:

Scheme 17 shows a synthetic process for making embodiments of formula (I).

Scheme 17

To a stirred solution of ethyl 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (1.5 g, 5.84 mmol) in ethanol (12 mL) and CH2CI2 (3 mL) was added NaHCCb (1105 mg, 13.2 mmol) and 10% Pd on carbon (240 mg, 5.84 mmol). The reaction was affixed with a ¾ balloon, and stirred for 2.5 h at ambient temperature. After consumption of the starting material, the reaction was filtered through celite, and the filtrate concentrated in vacuo. Ethyl 5-methylthieno[2,3-d]pyrimidine-6-carboxylate (1.3 g, 5.85 mmol, 100% yield) was obtained as off white solid. ¾ NMR (400 MHz, DMSO- de) d 9.49 (s, 1H), 9.23 (s, 1H), 4.37 (q, J= 7.1 Hz, 2H), 2.79 (s, 3H), 1.35 (t, J= 7.2 Hz, 3H). MS (ESI) [M+H] ⁺ : 223.1 (ACN: MEOAc).

Example 18:

Scheme 18 shows a synthetic process for making embodiments of formula (I).

Scheme 18

Step 1

To a foil-covered flask containing a stirred solution of AgNCE (11.5 mg, 0.07 mmol) and ( H ₄ ) ₂ S ₂ 0 ₈ (616 mg, 2.7 mmol) in CH2CI2 (5 mL) : Water (5 mL) was added cyclopentylboronic acid (308mg, 2.7 mmol). Ethyl 5-methylthieno[2,3-d]pyrimidine-6- carboxylate (300 mg, 1.35 mmol) was then added, and stirring continued for 16 h at 25 °C. After this time, additional AgNCE (11.5 mg, 0.07 mmol), ( H ₄ ) ₂ S ₂ 0 ₈ (616 mg, 2.7 mmol), and cyclopentylboronic acid (308mg, 2.7 mmol) was added, and the reaction mixture stirred for 24 h. After consumption of the starting material, the reaction was diluted with CH2CI2 (200 mL), washed with water (2 x 20 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel chromatography, which afforded ethyl 4-cyclopentyl-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylate (130 mg, 0.45 mmol, 33.2% yield) as an off white solid. ¹ H NMR (400 MHz, Chloroform-d) d 9.01 (s, 1H), 4.40 (q, 7= 7.1 Hz, 2H), 3.99 (p, J = 7.9 Hz, 1H), 3.02 (s, 3H), 2.12-1.99 (m, 4H), 1.93 (s, 2H), 1.82-1.66 (m, 2H), 1.41 (t, J= 7.1 Hz, 3H). MS (ESI) [M+H] ⁺ : 290.9 (ACN: NH ₄ OAC).

Step 2

To a stirred solution of ethyl 4-cyclopentyl-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (130 mg, 0.45 mmol) in THF (4 mL) : Water (2 mL) was added LiOH monohydrate (57mg, 1.34 mmol) at 0 °C, followed by stirring at ambient temperature for 16h. After this time, the reaction mixture was concentrated in vacuo , diluted with water (30 mL) and acidified to pH 3-4 with citric acid. The aqueous solution was extracted with EtOAc (2 x 40 ml), washed with brine, and the combined organics concentrated under reduced pressure to afford 4-cyclopentyl-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (110 mg, 0.42 mmol, 93.7% yield) as off white solid.

Step 3

To a stirred solution of 4-cyclopentyl-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylic acid (60 mg, 0.23 mmol) dissolved in THF (5 mL) under N2 atmosphere were sequentially added l-(2-methoxy-6-methyl-4-pyridyl)-N-methyl-methanamine (38 mg, 0.23 mmol), iP^NEt (0.1 mL, 0.69 mmol), and HATU (130 mg, 0.34 mmol) at 0 °C. The reaction was stirred at this temperature for 10 min, then allowed to warm to ambient temperature and stirred 16 h. The reaction was quenched with ice cold water and extracted with CH2CI2 (20 mL x 2), and the combined organic layers washed with saturated NaCl solution (20 mL x 1). The organic layer was dried over anhydrous Na ₂ SC> ₄ , filtered, and concentrated to give the crude product. Prep-HPLC purification provided 4-cyclopentyl-N-[(2-methoxy-6-methyl-4-pyridyl)methyl]-N, 5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (23.7 mg, 0.058 mmol, 25.2% yield) as brown solid. 1H NMR: (400 MHz, DMSO-d6, 100°C) d 8.95 (s, 1H), 6.72 (s, 1H), 6.46 (s, 1H), 4.60 (s, 2H), 4.06-3.93 (m, 1H), 3.87 (s, 3H), 2.99 (s, 3H), 2.57 (s, 3H), 2.40 (s, 3H), 2.10-1.98 (m, 4H), 1.90-1.80 (m, 2H), 1.79-1.69 (m, 2H). MS (ESI) [M+H] ⁺ : 411.2 (ACN: HCOOH).

The following are examples of analogs prepared according to Scheme 18: 4-cyclopentyl -N-((3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)methyl)-N, 5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: ¹ H NMR-VT (400 MHz, DMSO- d6, 100 °C) d 8.94 (s, 1H), 8.05 (d, J = 4.8 Hz, 1H), 7.00 (d, J = 5.0 Hz, 1H), 4.61 (s, 2H), 4.17 (t, J = 5.4 Hz, 2H), 4.05-3.93 (m, 1H), 2.98 (s, 3H), 2.87 (t, J = 6.5 Hz, 2H), 2.57 (s, 3H), 2.03-2.01 (m, 6H), 1.90-1.82 (m, 2H), 1.79-1.68 (m, 2H). MS (ESI) [M+H] ⁺ : 423.2 (ACN: NH ₄ OAC).

4-cyclopentyl-N-((2-methoxypyridin-4-yl)methyl)-N,5-dimethyl thieno[2,3- d]pyrimidine-6-carboxamide: ¾ NMR (400 MHz, DMSO- is) d 8.96 (s, 1H), 8.16 (d, J= 5.2 Hz, 1H), 6.91-6.85 (m, 1H), 6.67 (s, 1H), 4.66 (s, 2H), 4.03-3.94 (m, 1H), 3.89 (s, 3H), 2.99 (s, 3H), 2.57 (s, 3H), 2.08-1.99 (m, 4H), 1.90-1.82 (m, 2H), 1.75- 1.72 (m, 2H). MS (ESI) [M+H] ⁺ : 397.2 (ACN: NH ₄ OAC).

Example 19:

Scheme 19 shows a synthetic process for making embodiments of the invention.

Scheme 19

Step 1

To a stirred solution of 4-chloro-N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (1000 mg, 2.76 mmol) in ethanol (8.6 mL) and CH2CI2 (8.6 mL) was added NaHCCE (177 mg, 2.1 mmol), followed by 10% Pd on carbon (120 mg, 1.13 mmol). The reaction was purged with nitrogen, and then stirred under a H2 balloon for 5 h. After this time, the reaction was filtered through celite, and the filtrate concentrated in vacuo. The crude product was then dissolved in 1,4-dioxane (10 mL), to which MnCE (1198 mg, 13.78 mmol) was added and stirred for 16h. At this time, the reaction was filtered through celite, and the filtrate concentrated under vacuum to afford N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2,3-d]pyrimidine-6- carboxamide (875 mg, 2.6549 mmol, 96.3% yield) as off-white solid. MS (ESI) [M+H] ⁺ : 329.3 (ACN: HCOOH).

Step 2 To foil-covered flask containing a stirred solution of (ML^SiOs (139 mg, 0.61 mmol) and AgNCb (26 mg, 0.15 mmol) in Water (5mL) was added spiro[3.3]heptane-2- carboxylic acid (0.01 mL, 0.61 mmol), and the mixture stirred for 15min. N-[(2-methoxy- 4-pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]pyrimidine-6-car boxamide (100 mg, 0.30 mmol) dissolved in CH2CI2 (5 mL) was then added, and the combined solution stirred at ambient temperature for 48h in the dark. After this time, the reaction was diluted with ethyl acetate (20 mL), and the reaction filtered through celite. The filtrate was partitioned, and the organic phase dried with over anhydrous INfeSCL, filtered, and concentrated under vacuum to afford crude product. Prep-HPLC returned purified product, which was

lyophilized to yield N-((2-methoxypyridin-4-yl)methyl)-N,5-dimethyl-4- (spiro[3.3]heptan-2-yl)thieno[2,3-d]pyrimidine-6-carboxamide (5 mg, 0.012 mmol, 3.9% yield) as a brown solid. ¾ NMR (400 MHz, DMSO-^e) d 8.99 (s, 1H), 8.15 (d, J= 5.3 Hz, 1H), 6.87 (d, J= 5.4 Hz, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 4.20 (t, J= 8.2 Hz, 1H), 3.89 (s, 3H), 2.99 (s, 3H), 2.63-2.52 (m, 2H), 2.52 (s, 3H), 2.47-2.37 (m, 2H), 2.21-2.11 (m,

2H), 1.99-1.92 (m, 2H), 1.88-1.78 (m, 2H). MS (ESI) [M+H] ⁺ : 423.4 (ACN: HCOOH).

The following are examples of analogs prepared according to Scheme 19:

4-(3-methoxycyclobutyl)-N-((2-methoxypyridin-4-yl)methyl)-N, 5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: 1H NMR (400 MHz, DMSO-d6) d 9.02 (s, 1H), 8.15 (d, J = 5.1 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 4.05-3.96 (m, 1H), 3.90 (s, 3H), 3.23 (s, 3H), 2.99 (s, 3H), 2.66-2.63 (m, 1H), 2.55 (s, 3H), 1.11-0.89 (m, 4H). MS (ESI) [M+H] ⁺ : 413.1 (ACN: MLOAc).

4-(4-methoxybicyclo[2.2.1]heptan-l-yl)-N-((2-methoxypyridin- 4-yl)methyl)-N,5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: HNMR-VT: (400 MHz, DMSO-d6, 100 °C) d 8.93 (s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 6.88 (s, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.30 (s, 3H), 2.99 (s, 3H), 2.59 (s, 3H), 2.30-2.20 (m, 2H), 2.18 (s, 2H), 2.16-2.04 (m, 2H), 2.01-1.88 (m, 2H), 1.82-1.71 (m, 2H). MS (ESI) [M+H] ⁺ : 453.2 (ACN: MLOAc).

- N-((2-methoxypyridin-4-yl)methyl)-N, 5-dimethyl -4-(2-(tetrahydrofuran-3- yl)ethyl)thieno[2,3-d]pyrimidine-6-carboxamide: lH NMR (400 MHz, DMSO-d6) d 8.94 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H), 6.68 (s, 1H), 4.66 (s, 2H), 3.89 (s, 3H), 3.88-3.80 (m, 1H), 3.84-3.71 (m, 1H), 3.71-3.60 (m, 1H), 3.39- 3.30 (m, 1H), 3.30-3.22 (m, 2H), 3.00 (s, 3H), 2.57 (s, 3H), 2.36-2.27 (m, 1H), 2.12- 2.01 (m, 1H), 1.95-1.84 (m, 2H), 1.61-1.51 (m, 1H). MS (ESI) [M+H] ⁺ : 427.1 (ACN: MLOAc). 4-(7-oxabicyclo[2.2.1]heptan-2-yl)-N-((2-methoxypyridin-4-yl )methyl)-N,5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: 1H NMR (400 MHz, DMSO-d6) d

8.95 (s, 1H), 8.16 (s, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 4.73-4.62 (m, 4H), 3.89 (s, 4H), 3.00 (s, 3H), 2.56 (s, 3H), 1.91-1.58 (m, 6H). MS (ESI) [M+H] ⁺ : 425.2 (ACN:

MEOAc).

4-(8-oxabicyclo[3.2.1]octan-3-yl)-N-((2-methoxypyridin-4-yl) methyl)-N,5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: 1H NMR (400 MHz, DMSO-d6) d 8.98 (s, 1H), 8.16 (s, 1H), 6.89 (s, 1H), 6.68 (s, 1H), 4.66 (s, 2H), 4.44 (s, 2H), 4.11-

3.95 (m, 1H), 3.89 (s, 3H), 3.00 (s, 3H), 2.62 (s, 3H), 2.18 (t, J = 12.5 Hz, 2H), 2.02- 1.89 (m, 4H), 1.71-1.61 (m, 2H). MS (ESI) [M+H] ⁺ : 439.4 (ACN: MEOAc).

4-(5,5-dimethyltetrahydrofuran-3-yl)-N-((2-methoxypyridin -4-yl)methyl)-N,5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: ¾ NMR (400 MHz, DMSO- is) d 9.04 (s, 1H), 8.25-8.08 (m, 1H), 7.01-6.52 (m, 2H), 4.77-4.34 (m, 3H), 4.24-4.12 (m, 1H), 4.10-4.00 (m, 1H), 3.86 (s, 3H), 3.07-2.88 (m, 3H), 2.59 (s, 3H), 2.22

(d, J= 8.7 Hz, 2H), 1.36-1.26 (m, 6H). MS (ESI) [M+H] ⁺ : 427.3 (ACN: MEOAc).

4-(4-methoxycyclohexyl)-N-((2-methoxypyridin-4-yl)methyl) -N,5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide:

o Isomer 1 : 1H NMR (400 MHz, DMSO-d6) d 8.96 (s, 1H), 8.16 (d, J = 5.2 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H), 6.67 (s, 1H), 4.66 (s, 2H), 3.89 (s, 3H), 3.50- 3.44 (m, 1H), 3.31 (s, 3H), 3.28-3.20 (m, 1H), 2.56 (s, 3H), 2.20-2.12 (m,

2H), 1.97-1.75 (m, 4H), 1.43-1.25 (m, 2H). MS (ESI) [M+H] ⁺ : 441.4 (ACN: MEOAc).

o Isomer 2: 1H NMR (400 MHz, DMSO-d6) d 8.96 (s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 4.8 Hz, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.55- 3.49 (m, 2H), 3.29 (s, 3H), 2.56 (s, 3H), 2.10-1.98 (m, 4H), 1.64-1.60 (m,

4H). MS (ESI) [M+H] ⁺ : 441.4 (ACN: MEOAc).

4-(4-ethylcyclohexyl)-N-((2-methoxypyridin-4-yl)methyl)-N ,5-dimethylthieno[2,3- d]pyrimidine-6-carboxamide: lH NMR (400 MHz, DMSO-d6) d 8.95 (s, 1H), 8.15 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 5.0 Hz, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.65-3.34 (m, 2H), 3.00 (s, 3H), 2.56 (s, 3H), 1.99-1.83 (m, 2H), 1.77-1.61 (m, 4H), 1.51-1.43 (m, 1H), 1.34-1.26 (m, 2H), 1.21-1.13 (m, 1H), 0.93 (t, J = 7.3 Hz, 3H).

MS (ESI) [M+H] ⁺ : 439.0 (ACN: HCOOH).

N-((2-methoxypyridin-4-yl)methyl)-N, 5-dimethyl -4-phenethylthieno[2, 3- d]pyrimidine-6-carboxamide: lH NMR (400 MHz, DMSO-d6): d 8.98 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 7.30-7.20 (m, 4H), 7.21-7.14 (m, 1H), 6.87 (d, J = 5.3 Hz, 1H), 6.67 (s, 1H), 4.63 (s, 2H), 3.89 (s, 3H), 3.60-3.51 (m, 2H), 3.21-3.12 (m, 2H), 2.97 (s, 3H). MS (ESI) [M+H] ⁺ : 432.9 (ACN: HCOOH).

N-((2-methoxypyridin-4-yl)methyl)-N, 5-dimethyl -4-(phenoxymethyl)thieno[2, 3- d]pyrimidine-6-carboxamide: 1H NMR (400 MHz, DMSO-d6) d 9.07 (s, 1H), 8.15 (d, J = 5.3 Hz, 1H), 7.31 (t, J = 7.9 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H), 6.97-6.86 (m, 2H), 6.68 (s, 1H), 5.58 (s, 2H), 4.66 (s, 2H), 3.88 (s, 3H), 3.00 (s, 3H), 2.56 (s, 3H). MS (ESI) [M+H] ⁺ : 435.0 (ACN: HCOOH).

- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-tetrahydropyr an-3-yl-thieno[2,3- d]pyrimidine-6-carboxamide: 1H MR (400 MHz, DMSO-d6) d 8.97 (s, 1H), 8.16 (d, J = 5.3 Hz, 1H), 6.89 (s, 1H), 6.67 (s, 1H), 4.66 (s, 2H), 4.05 (d, J = 6.7 Hz, 1H), 3.99-3.91 (m, 1H), 3.89 (s, 3H), 3.72 (d, J = 6.9 Hz, 2H), 3.49-3.38 (m, 1H), 2.99 (s, 3H), 2.58 (s, 3H), 2.06-2.01 (m, 2H), 1.77-1.71 (m, 2H), 1.27 (s, 1H). MS (ESI) [M+H] ⁺ : 413.2 (ACN: HCOOH).

4-cyclobutyl-N-((2-methoxypyridin-4-yl)methyl)-N,5-dimethylt hieno[2,3- d]pyrimidine-6-carboxamide: lH NMR (400 MHz, DMSO-d6) d 9.01 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 6.86 (d, J = 5.2 Hz, 1H), 6.65 (s, 1H), 4.63 (s, 2H), 4.41-4.31 (m,

1H), 3.88 (s, 3H), 2.98 (s, 3H), 2.64-2.52 (m, 2H), 2.52 (s, 3H), 2.45-2.32 (m, 2H), 2.16-2.00 (m, 1H), 2.04-1.87 (m, 1H).

Example 20:

Scheme 20 shows a synthetic process for making embodiments of formula (I).

Scheme 20

Step 1

To a stirred solution of ethyl 5-methylthieno[2,3-d]pyrimidine-6-carboxylate (100 mg, 0.45 mmol) in DMSO (12 mL) was added (NH^SiOs (205 mg, 0.90 mmol) and 3- cyclopentylpropanoic acid (320 mg, 2.25 mmol). The reaction was then degassed for 5 min with N2. [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (6.6 mg, 0.01 mmol) was then added, and the reaction photolyzed with a 3.4 Watt blue LED light for 24h. At this time, the reaction was quenched by the addition of ice water (30 mL), stirred for 30 min, and extracted into ethyl acetate (10 mL x 2). The combined organics were dried over anhydrous NaiSCL, filtered, and concentration to afford crude product, which was purified with 100-200 mesh silica gel to afford ethyl 4-(2-cyclopentylethyl)-5-methyl-thieno[2,3-d]pyrimidine- 6-carboxylate (72 mg, 0.23 mmol, 50.3% yield) as off-white solid. 1H NMR (400 MHz, DMSO-de) 59.042(s,lH), d 4.37 (q, 7= 7.1 Hz, 1H), 2.18 (t, J= 7.7 Hz, 2H), 1.86-1.65 (m, 5H), 1.64-1.41 (m, 9H), 1.34 (t, J= 7.1 Hz, 2H), 1.23-0.97 (m, 3H). MS (ESI)

[M+H] ⁺ : 319.1 (ACN: HCOOH).

Step 2

To a stirred solution of ethyl 4-(2-cyclopentylethyl)-5-methyl-thieno[2,3- d]pyrimidine-6-carboxylate (72 mg, 0.23 mmol) in THF (1 mL) : Water (1 mL) was added LiOH monohydrate (16.25 mg, 0.68 mmol) at 0 °C. The ice bath was removed, and the reaction mixture stirred at 40 °C for 2h. After this time, the reaction mixture was cooled to 0 °C and made acidic (pH = 1) with IN HC1. The solution was extracted with 10% MeOH-DCM solution (3 x 50mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 4-(2-cyclopentylethyl)-5-methyl-thieno[2,3- d]pyrimidine-6-carboxylic acid (40 mg, 0.12 mmol, 51.8% yield) as an off-white solid. ¾ NMR (400 MHz, DMSO-de) d 9.02 (s, 1H), 2.96 (s, 3H), 1.87-1.66 (m, 5H), 1.66- 1.40 (m, 8H). MS (ESI) (M-H)+: 289.3 (ACN: HCOOH).

Step 3

To a stirred solution of 4-(2-cyclopentylethyl)-5-methyl-thieno[2,3-d]pyrimidine- 6-carboxylic acid (40 mg, 0.14 mmol) dissolved in THF (2 mL) under N2 atmosphere were sequentially added l-(2-methoxy-4-pyridyl)-N-methyl-methanamine.HCl (52 mg, 0.28 mmol), iPriNEt (72.2 mL, 0.41 mmol), and HATU (78.6 mg, 0.21 mmol) at 0°C.

The reaction was stirred for 10 min at this temperature, then allowed to gradually warm to ambient temperature for 16h. After this time, the reaction mixture was quenched with ice cold water and stirred for 20 min, and extracted with ethyl acetate (3 x 50mL) . The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 4-(2-cyclopentylethyl)- N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]py rimidine-6-carboxamide (20.6 mg, 0.048 mmol, 35.1% yield) as off-white gum: lH NMR (400 MHz, DMSO-d6) d 8.93 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 6.91-6.85 (m, 1H), 6.67 (s, 1H), 4.65 (s, 2H),

3.89 (s, 3H), 3.23 (t, J = 7.7 Hz, 2H), 3.00 (s, 3H), 2.56 (s, 3H), 2.02-1.89 (m, 1H), 1.81 (q, J = 7.8 Hz, 4H), 1.68-1.48 (m, 4H), 1.25-1.17 (m, 2H). MS (ESI) [M+H] ⁺ : 425.2

(ACN: HCOOH).

The following are examples of analogs prepared according to Scheme 20:

4-(2-cyclohexylethyl)-N-((2-methoxypyridin-4-yl)methyl)-N,5- dimethylthieno[2,3- d]pyrimidine-6-carboxamide: H NMR (400 MHz, DMSO- _< 76) d 8.92 (s, 1H), 8.15 (d, J= 5.2 Hz, 1H), 6.88 (d, J= 5.4 Hz, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.26-3.17 (m, 2H), 3.00 (s, 3H), 2.55 (s, 3H), 1.79 (d, J= 12.8 Hz, 2H), 1.75-1.60 (m, 5H), 1.52-1.37 (m, 1H), 1.31-1.18 (m, 3H), 1.09-0.95 (m, 2H). MS (ESI)

[M+H] ⁺ : 439.2 (ACN: NH ₄ OAc).

N-((2-methoxypyridin-4-yl)methyl)-N, 5-dimethyl -4-(4, 4, 4-trifluorobutyl)thieno[2, 3- d]pyrimidine-6-carboxamide: 1H MR (400 MHz, DMSO-d6) d 8.92 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 6.88 (d, J = 5.4 Hz, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.26-3.17 (m, 2H), 3.00 (s, 3H), 2.55 (s, 3H), 1.79 (d, J = 12.8 Hz, 2H), 1.75-1.60 (m, 5H), 1.52-1.37 (m, 1H), 1.31-1.18 (m, 3H), 1.09-0.95 (m, 2H). MS (ESI) [M+H] ⁺ : 439.4 (ACN: NH ₄ OAc).

4-(3-hydroxycyclobutyl)-N-((2-methoxypyridin-4-yl)methyl)-N, 5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: lH NMR (400 MHz, DMSO-d6) d 9.02 (s, 1H), 8.15 (d, J = 5.2 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 6.67 (s, 1H), 4.85-4.73 (m, 1H), 4.65 (s, 2H), 4.32-4.15 (m, 1H), 3.89 (s, 3H), 3.82-3.71 (m, 1H), 2.99 (s, 3H), 2.69-2.56 (m, 2H), 2.55 (s, 3H), 2.47-2.35 (m, 2H). MS (ESI) [M+H] ⁺ : 399.3 (ACN: NH ₄ OAC).

4-(3,3-difluorocyclopentyl)-N-((2-methoxypyridin-4-yl)methyl )-N,5- dimethylthieno[2,3-d]pyrimidine-6-carboxamide: ¾ NMR (400 MHz, DMSO-d ₆ ) d 9.02 (s, 1H), 8.16 (d, J = 5.4 Hz, 1H), 6.88 (d, J= 5.2 Hz, 1H), 6.68 (s, 1H), 4.66 (s, 2H), 4.29 (t, J= 7.8 Hz, 1H), 3.89 (s, 3H), 3.00 (s, 3H), 2.86-2.63 (m, 1H), 2.58 (s, 3H), 2.46-2.07 (m, 5H). MS (ESI) [M+H] ⁺ : 433.2 (ACN: NH ₄ OAc).

Example 21:

Scheme 21 shows a synthetic process for making embodiments of formula (I).

Scheme 21

Step 1

To a stirred solution of 4-chloro-N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (1.0 g, 2.76 mmol) and benzaldehyde (351mg, 3.31 mmol) in THF (15 mL) was added 1,3-dimethylimidazolium iodide (216 mg, 0.96 mmol) and NaH (132 mg, 5.5 mmol) at 0 °C. The reaction was refluxed for 1 hr, and the progress of the reaction was monitored by TLC and LCMS. The reaction was quenched with ice-water and extracted with ethyl acetate (50 ml x 2). The combined organic layer dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude product, which was purified by silica gel chromatography (ethyl acetate : hexanes) to afford 4- benzoyl-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3-d]pyrimidine-6- carboxamide (500 mg, 1.156 mmol, 41.9% yield). ¹ H NMR (400 MHz, DMSO- is) d 9.25 (s, 1H), 8.14 (s, 1H), 7.90 (s, 2H), 7.78 (d, J= 7.4 Hz, 1H), 7.60 (t, J= 7.7 Hz, 2H), 6.98- 6.80 (m, 1H), 6.79-6.63 (m, 1H), 4.75-4.49 (m, 2H), 3.84 (s, 3H), 2.94 (s, 3H), 2.05 (s, 3H). MS (ESI) [M+H] ⁺ : 433.0 (ACN: NH ₄ OAc).

Step 2

To a stirred solution of 4-benzoyl-N-[(2-methoxy-4-pyridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (600 mg, 1.39 mmol) in THF (6 mL) was added methanol (1 mL) and NaBH4 (26.24 mg, 0.69 mmol) at 0 °C. The reaction was stirred at 0 °C for 1 hr, and the progress of the reaction was monitored by TLC and LCMS. After this time, the reaction was quenched with ice-water and extracted with ethyl acetate (50 ml x 2). The combined organic layer dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude product, which was purified by silica gel chromatography (ethyl acetate : hexanes) to afford 4-[hydroxy(phenyl)methyl]-N-[(2- methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2,3-d]pyrimidine-6-carboxamide (350 mg, 0.81 mmol, 58.1% yield). ¾ NMR (400 MHz, DMSO-de) d 9.05 (s, 1H), 8.21-8.14 (m, 1H), 7.40-7.24 (m, 5H), 6.98-6.71 (m, 1H), 6.73-6.59 (m, 1H), 6.40 (s, 2H), 4.75- 4.49 (m, 2H), 3.85 (s, 3H), 3.04-2.85 (m, 3H). MS (ESI) [M+H] ⁺ : 435.3 (ACN:

MEOAc).

Step 3

To a stirred solution of 4-[hydroxy(phenyl)methyl]-N-[(2-methoxy-4- pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carbo xamide (40 mg, 0.09 mmol) in THF (0.40 mL) was added Deoxofluor (102 mg, 0.46 mmol) at 0 °C. The reaction removed from the ice bath, and heated to 90 °C. After the starting material was consumed, the reaction was quenched with ice-water and extracted with ethyl acetate (50 ml x 2). The combined organic layer dried over anhydrous sodium sulfate, filtered, and concentrated to yield crude product, which was purified by silica gel chromatography (ethyl acetate : hexanes) to afford 4-[fluoro(phenyl)methyl]-N-[(2-methoxy-4- pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carbo xamide (12 mg, 0.027 mmol, 29.50% yield): 1H NMR (400 MHz, DMSO-d6) d 9.20-9.15 (m, 1H), 8.20-8.15 (m, 1H), 7.45-7.28 (m, 5H), 6.97-6.91 (m, 1H), 6.77-6.71 (m, 1H), 6.62-6.54 (m, 1H), 4.70-4.68 (m, 1H), 4.57-4.51 (m, 1H), 3.85 (s, 3H), 3.05-2.86 (m, 3H), 2.46 (s, 3H). MS (ESI) [M+H] ⁺ : 436.9 (ACN: MEOAc).

Example 22: Scheme 22 shows a synthetic process for making embodiments of formula (I).

Step 1

To a stirred solution of 4-[hydroxy(phenyl)methyl]-N-[(2-methoxy-4- pyridyl)methyl]-N,5-dimethyl-thieno[2,3-d]pyrimidine-6-carbo xamide (50 mg, 0.12 mmol) in CH2CI2 (0.12 mL) were added sequentially triethylamine (0.03 mL, 0.23 mmol) and methanesulfonyl chloride (0.01 mL, 0.17 mmol) at 0 °C under nitrogen. The reaction was allowed to gradually warm to ambient temperature, and stirred for 18h. At this time, the reaction was quenched with ice-water and extracted with ethyl acetate (25 ml x 2). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was used in next step without further purification: MS (ESI) [M+H] ⁺ : 513.2 (ACN: NEEOAc).

Step 2

To a stirred solution of [[6-[(2-methoxy-4-pyridyl)methyl-methyl-carbamoyl]-5- methyl-thieno[2,3-d]pyrimidin-4-yl]-phenyl-methyl] methanesulfonate (150 mg, 0.29 mmol) in THF (3mL) was added methanol (0.50 mL) and NaBH4 (5.54 mg, 0.15 mmol) at 0 °C. The reaction was stirred at 90 °C for 16 hr, after which time it was quenched with ice-water and extracted with ethyl acetate (25ml x 2). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to afford 4- benzyl-N-[(2-methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2, 3-d]pyrimidine-6- carboxamide (19 mg, 0.045 mmol, 15.5% yield): 1H NMR (400 MHz, DMSO-d6) d 9.02 (s, 1H), 8.17 (s, 1H), 7.34-7.18 (m, 3H), 7.16 (s, 2H), 6.98-6.55 (m, 2H), 4.75-4.47 (m, 4H), 3.85 (s, 3H), 3.04-2.84 (m, 3H). MS (ESI) (M)+: 418.8 (ACN: MEOAc).

Example 23:

Scheme 23 shows a synthetic process for making embodiments of formula (I).

To a stirred solution of 4-benzoyl-N-[(2-methoxy-4-pyridyl)methyl]-N,5- dimethyl-thieno[2,3-d]pyrimidine-6-carboxamide (50 mg, 0.12 mmol) in THF (0.50 mL) was added MeMgBr (1.0M solution in THF, 17 mg, 0.14 mmol) at 0 °C. The reaction was then removed from the ice bath, and stirred at ambient temperature for 4 hrs. After this time, the reaction was cooled to 0 °C and quenched with ammonium chloride solution.

The solution was extracted with ethyl acetate (25 ml x 2), and the combined organics were washed with brine solution, dried over anhydrous sodium sulfate, filtered, and the volatiles removed under vacuum. The crude product was purified by silica gel

chromatography (hexane/ethyl acetate) to afford 4-(l-hydroxy-l-phenyl-ethyl)-N-[(2- methoxy-4-pyridyl)methyl]-N, 5-dimethyl -thieno[2,3-d]pyrimidine-6-carboxamide (12 mg, 0.025 mmol, 38.5% yield) as off white solid: 1H MR (400 MHz, DMSO-d6) d 9.16 (s, 1H), 8.14 (s, 1H), 7.27 (s, 2H), 7.21 (s, 2H), 6.91-6.82 (m, 1H), 6.69-6.64 (m, 1H), 6.54-6.49 (m, 1H), 4.65-4.59 (m, 2H), 4.40-4.33 (m, 1H), 3.84 (s, 3H), 2.95-2.88 (m, 2H), 2.76 (s, 2H), 1.93-1.87 (m, 5H). MS (ESI) [M+H] ⁺ : 449.2 (ACN: MLOAc).

Example 24:

Scheme 24 shows a synthetic process for making embodiments of formula (I).

Scheme 24

Step 1

To a stirred solution of ethyl 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6- carboxylate (1.0 g, 3.9 mmol) and K2CO3 (1346mg, 9.74 mmol) in 1,4-dioxane (20 mL) were added P(Cy) ₃ (219mg, 0.78 mmol) and Pd ₂ dba ₃ (357mg, 0.39 mmol). The solution was de-gassed for 5 minutes with nitrogen, after which time 2-(2,5-dihydrofuran-3-yl)- 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (916 mg, 4.67 mmol) was added. The reaction mixture was then heated at 110 °C for 16h. After completion of the reaction, the reaction was passed through celite, and further eluted with ethyl acetate (2 x 50 mL). The filtrate was washed with water (30 mL), and the organic layer washed with saturated NaCl (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (40% EtOAc in hexane) to give ethyl 4-(2,5-dihydrofuran-3-yl)-5-methyl-thieno[2,3-d]pyrimidine-6 -carboxylate (650 mg, 2.24 mmol, 57.5% yield) as an off-white solid. ¾ NMR (400 MHz, DMSO- is) 5 9.13 (s, 1H), 6.54 - 6.48 (m, 1H), 5.10-5.01 (m, 2H), 4.92-4.84 (m, 2H), 4.38 (q, J= 7.1 Hz,

2H), 2.75 (s, 3H), 1.34 (t, J= 7.0 Hz, 3H). MS (ESI) [M+H] ⁺ : 290.9 (ACN: MLOAc).

Step 2

A solution of ethyl 4-(2,5-dihydrofuran-3-yl)-5-methyl-thieno[2,3-d]pyrimidine-6 - carboxylate (385 mg, 1.33 mmol) in a 1 : 1 mixture of methanol (5m L) and ethanol (5 mL), was degassed for 5 minutes with Argon. 10% Pd on Carbon (282 mg, 2.65 mmol) was added, and reaction stirred under H2 balloon for lh. At this time, the reaction mixture was filtered through celite and further eluted with EtOAc. The filtrate was evaporated to dryness to get afford ethyl 5-methyl-4-tetrahydrofuran-3-yl-thieno[2,3-d]pyrimidine-6- carboxylate (350 mg, 1.20 mmol, 90.28% yield): ¾NMR (400 MHz, Chloroform-t ) d 9.06 (s, 1H), 4.46-4.30 (m, 3H), 4.21 (t, J= 7.9 Hz, 1H), 4.18-4.09 (m, 2H), 4.02 (q, J = 7.5 Hz, 1H), 3.02 (s, 3H), 2.55-2.42 (m, 1H), 2.43-2.30 (m, 1H), 1.42 (t, J= 7.1 Hz, 3H). MS (ESI) [M+H] ⁺ : 293.1 (ACN: MEOAc).

Step 3

To a stirred solution of ethyl 5-methyl-4-tetrahydrofuran-3-yl-thieno[2,3- d]pyrimidine-6-carboxylate (350 mg, 1.2 mmol) in a 1 :2 mixture of THF (10 mL) : Water (5 mL) was added LiOH monohydrate (86 mg, 3.59 mmol) at 0° C. The reaction was removed from the ice bath and stirred overnight at ambient temperature. After

completion, the reaction mixture was evaporated to dryness, diluted with water, and acidified to pH 4-5 by the addition of saturated aqueous citric acid. The mixture was extracted with 10% MeOH/DCM solution (25 ml x 2), and the combined organic layers evaporated under reduced pressure to afford 5-methyl-4-tetrahydrofuran-3-yl-thieno[2,3- d]pyrimidine-6-carboxylic acid (315 mg, 1.192 mmol, 99.6% yield). MS (ESI) [M+H] ⁺ : 265.1 (ACN: MEOAc).

Step 4

To a stirred solution of 5-methyl-4-tetrahydrofuran-3-yl-thieno[2,3-d]pyrimidine- 6-carboxylic acid (80 mg, 0.30 mmol) in THF (5.41mL), were sequentially added N- methyl-l-(l,8-naphthyridin-4-yl)methanamine (52 mg, 0.30 mmol), iP^NEt (0.13 mL, 0.91 mmol) and HATU (173mg, 0.45 mmol) at 0 °C under an atmosphere of N2. After 10 minutes, the flask was removed from the ice bath and stirred at ambient temperature for 16 h. At this time, the reaction was quenched with ice water and extracted with CH2CI2 (20 mL x 2). The combined organic phases were washed with saturated NaCl solution, dried over anhydrous Na2SC>4, filtered, and the solvent removed under reduced pressure. The crude product was purified by prep-HPLC to give a yield N,5-dimethyl-N-(l,8- naphthyridin-4-ylmethyl)-4-tetrahydrofuran-3-yl-thieno[2,3-d ]pyrimidine-6-carboxamide (22 mg, 0.052 mmol, 17.3% yield): 1H MR (400 MHz, DMSO-d6) d 9.12 (d, J = 4.3 Hz, 2H), 8.98 (s, 1H), 8.68-8.60 (m, 1H), 7.69-7.62 (m, 1H), 7.55 (d, J = 4.4 Hz, 1H), 5.27 (s, 2H), 4.35-4.25 (m, 1H), 4.13 (t, J = 7.9 Hz, 1H), 4.04-3.84 (m, 3H), 3.04 (s, 3H), 2.56 (s, 3H), 2.41-2.28 (m, 2H). MS (ESI) [M+H] ⁺ : 420.3 (ACN: NH ₄ OAc). The following are examples of analogs prepared according to Scheme 24:

- N-((3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)methyl)-N,5-dim ethyl-4- (tetrahydrofuran-3-yl)thieno[2,3-d]pyrimidine-6-carboxamide: 1H NMR (400 MHz, DMSO-d6) d 9.00 (s, 1H), 8.06 (d, J = 4.8 Hz, 1H), 7.02 (d, J = 4.9 Hz, 1H), 4.61 (s, 2H), 4.37-4.29 (m, 1H), 4.19-4.14 (m, 2H), 3.90 (d, J = 7.6 Hz, 1H), 3.18-3.02 (m, 4H), 2.97 (s, 3H), 2.90-2.84 (m, 2H), 2.58 (s, 3H), 2.39-2.32 (m, 2H), 2.03 (s, 2H). MS (ESI) [M+H] ⁺ : 425.0 (ACN: NH ₄ OAc).

- N-((2-ethylpyridin-4-yl)methyl)-N,5-dimethyl-4-(tetrahydrofu ran-3-yl)thieno[2,3- d]pyrimidine-6-carboxamide: 1H NMR-VT (400 MHz, DMSO-d6) d 8.99 (s, 1H),

8.46 (d, J = 5.0 Hz, 1H), 7.15-7.05 (m, 2H), 4.68 (s, 2H), 4.32 (q, J = 7.5 Hz, 1H),

4.15 (t, J = 7.9 Hz, 1H), 4.00 (q, J = 7.5 Hz, 2H), 3.90 (q, J = 7.4 Hz, 1H), 3.01 (s,

3H), 2.78 (q, J = 7.5 Hz, 2H), 2.58 (s, 3H), 2.44-2.27 (m, 2H), 1.25 (t, J = 7.7 Hz,

3H). MS (ESI) [M+H] ⁺ : 397.0 (ACN: MROAc).

N-((2-methoxy-6-methylpyridin-4-yl)methyl)-N, 5-dimethyl -4-(tetrahy drofuran-3- yl)thieno[2,3-d]pyrimidine-6-carboxamide: 1H MR -VT (400 MHz, DMSO-d6) d 8.99 (s, 1H), 6.72 (s, 1H), 6.46 (s, 1H), 4.61 (s, 2H), 4.39-4.27 (m, 1H), 4.15 (t, J =

7.9 Hz, 1H), 4.05-3.94 (m, 2H), 3.94-3.89 (m, 1H), 3.87 (s, 3H), 2.99 (s, 3H), 2.58 (s, 3H), 2.40 (s, 3H), 2.44-2.28 (m, 2H). MS (ESI) [M+H] ⁺ : 413.3 (ACN: MROAc). N-((2-m ethoxy quinolin-4-yl)methyl)-N,5-dimethyl-4-(tetrahydrofuran-3- yl)thieno[2,3-d]pyrimidine-6-carboxamide: lH NMlH NMR-VT (400 MHz, DMSO- d6) d 8.98 (s, 1H), 8.03-7.98 (m, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.69 (t, J = 7.7 Hz,

1H), 7.47 (d, J = 7.7 Hz, 1H), 6.91 (s, 1H), 5.16 (s, 2H), 4.36-4.27 (m, 1H), 4.14 (t, J = 7.9 Hz, 1H), 4.04 (s, 3H), 3.97 (t, J = 7.5 Hz, 2H), 3.89 (q, J = 7.0 Hz, 1H), 3.02 (s, 3H), 2.57 (s, 3H), 2.39-2.30 (m, 2H). MS (ESI) [M+H] ⁺ : 449.4 (ACN: MROAc).

- N,5-dimethyl-N-((2-methylquinolin-4-yl)methyl)-4-(tetrahydro furan-3-yl)thieno[2,3- d]pyrimidine-6-carboxamide: lH NMR (400 MHz, DMSO-d6) d 8.98 (s, 1H), 8.09- 8.04 (m, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.73 (t, J = 7.9 Hz, 1H), 7.55 (t, J = 7.7 Hz,

1H), 7.32 (s, 1H), 5.19 (s, 2H), 4.30 (q, J = 7.3 Hz, 1H), 4.13 (t, J = 7.9 Hz, 1H), 4.02-3.93 (m, 2H), 3.89 (q, J = 7.4 Hz, 1H), 3.18-3.01 (m, 3H), 2.69 (s, 3H), 2.56 (s, 3H), 2.37-2.31 (m, 2H). MS (ESI) [M+H] ⁺ : 432.8 (ACN: MROAc).

- N,5-dimethyl-N-(4-quinolylmethyl)-4-tetrahydrofuran-3-yl-thi eno[2,3-d]pyrimidine- 6-carboxamide: lH NMR (400 MHz, DMSO-d6) d 8.98 (s, 1H), 8.93 (d, J = 4.4 Hz, 1H), 8.17-8.11 (m, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.79 (t, J = 7.7 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 4.4 Hz, 1H), 5.24 (s, 2H), 4.35-4.26 (m, 1H), 4.13 (t, J = 7.9 Hz, 1H), 4.03-3.94 (m, 2H), 3.98-3.83 (m, 1H), 3.03 (s, 3H), 2.57 (s, 3H), 2.36-2.31 (m, 2H). MS (ESI) [M+H] ⁺ : 419.1 (ACN: MEOAc).

Example 25: Scheme 25 shows a synthetic process for making embodiments of formula (I).

Scheme 25

Step 1

To a stirred solution of 4-chloro-N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl- thieno[2,3-d]pyrimidine-6-carboxamide (300 mg, 0.83 mmol) and K2CO3 (286mg, 2.07 mmol) in 1,4-dioxane (6 mL) were added tert-butyl 4-(4, 4,5,5 -tetram ethyl -1,3,2- dioxaborolan-2-yl)-3,6-dihydropyridine-l(2H)-carboxylate (306 mg, 0.99 mmol), P(Cy)3 (46 mg, 0.17 mmol), and Pd ₂ dba ₃ (76 mg, 0.08 mmol). The flask was degassed under Argon for 5 minutes, then heated at 110 °C for 16h. After completion of the reaction, the catalyst was filtered off through celite, and eluted with ethyl acetate (2 x 20 mL). The filtrate was concentrated in vacuo to afford crude product, which was purified by silica gel chromatography (40% EtOAc in hexane) to yield tert-butyl 4-[6-[(2-methoxy-4- pyridyl)methyl-methyl-carbamoyl]-5-methyl-thieno[2,3-d]pyrim idin-4-yl]-3, 6-dihydro- 2H-pyridine-l-carboxylate (300 mg, 0.589 mmol, 71.2% yield) as a light yellow solid. MS (ESI) [M+H] ⁺ : 510.0 (ACN: MEOAc).

Step 2

A stirred solution of tert-butyl 4-[6-[(2-methoxy-4-pyridyl)methyl-methyl- carbamoyl]-5-methyl-thieno[2,3-d]pyrimidin-4-yl]-3,6-dihydro -2H-pyridine-l- carboxylate (120 mg, 0.24 mmol) in methanol (3.7 mL) was purged with N2, followed by the addition of 10% Pd on Carbon (120 mg, 0.11 mmol). The reaction mixture was then stirred for 16 h at ambient temperature in Parr shaker apparatus under 50 psi H2 pressure. After completion of the reaction, the reaction was filtered through celite, further eluted with ethyl acetate (2 x 10 mL), and concentrated in vacuo to afford tert-butyl 4-[6-[(2- methoxy-4-pyridyl)methyl-methyl-carbamoyl]-5-methyl-thieno[2 ,3-d]pyrimidin-4- yl]piperidine-l -carboxylate (100 mg, 0.195 mmol, 83 % yield) as an off-white gum: ¾ NMR (400 MHz, DMSO-^e) d 8.98 (s, 1H), 8.16 (d, J= 5.3 Hz, 1H), 6.88 (s, 1H), 6.68 (s, 1H), 4.66 (s, 2H), 4.10 (d, J= 13.5 Hz, 2H), 3.75-3.65 (m, 1H), 2.95 (s, 4H), 2.58 (s, 3H), 2.09-1.95 (m, 1H), 1.89-1.78 (m, 4H), 1.45 (s, 9H), 1.41 (s, 3H). MS (ESI) [M+H] ⁺ : 512.4 (ACN: MLOAc).

Step 3

To a stirred solution of tert-butyl 4-[6-[(2-methoxy-4-pyridyl)methyl-methyl- carbamoyl]-5-methyl-thieno[2,3-d]pyrimidin-4-yl]piperidine-l -carboxylate (400 mg, 0.78 mmol) in CH2CI2 (20 mL) was added trifluoroacetic acid (0.3 mL, 3.91 mmol) dropwise at 0 °C. After stirring 2h at ambient temperature, the reaction mixture was concentrated to dryness and triturated with pentane (3 x) to get the afford N-[(2-methoxy-4- pyridyl)methyl]-N, 5-dimethyl -4-(4-piperidyl)thieno[2,3-d]pyrimidine-6-carboxamide, trifluoroacetate salt (300 mg, 0.73 mmol, 93.2% yield) as a yellow oil: MS (ESI) [M+H] ⁺ : 412.1 (ACN: HCOOH).

Step 4

To a stirred solution of N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(4- piperidyl)thieno[2,3-d]pyrimidine-6-carboxamide (100. mg, 0.24 mmol) in 1,4-dioxane (4 mL) were added CS2CO3 (238 mg, 0.73 mmol) and l-iodo-4-(trifluoromethyl)benzene (99 mg, 0.36 mmol). The mixture was degassed with argon for 5 min, after which time Pd ₂ dba ₃ (22.3 mg, 0.02 mmol) and XPhos Pd G3 (41.1 mg, 0.05 mmol) were added, and the reaction mixture and further degassed with argon for 5 min. The reaction mixture was heated at 110 °C for 16 h. After that the reaction mixture was filtered through celite, washed with ethyl acetate (2 x 20 mL). The filtrate was washed with water (2 x 20mL), followed by saturated NaCl (20 mL), and the organic phase dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material was purified by prep-HPLC to afford N-((2-methoxypyridin-4-yl)methyl)-N,5-dimethyl-4-(l-(4- (trifluoromethyl)phenyl)piperidin-4-yl)thieno[2,3-d]pyrimidi ne-6-carboxamide (12 mg, 0.02 mmol, 8.76% yield) as off white solid: ¾ NMR (400 MHz, DMSO-de) d 8.97 (s, 1H), 8.16 (d, J= 5.2 Hz, 1H), 7.50 (d, J= 8.7 Hz, 2H), 7.09 (d, J= 8.7 Hz, 2H), 6.89 (d, J = 5.4 Hz, 1H), 6.68 (s, 1H), 4.67 (s, 2H), 4.02 (d, J= 12.9 Hz, 2H), 3.90 (s, 3H), 3.86- 3.74 (m, 1H), 3.12 (t, J = 11.8 Hz, 2H), 3.01 (s, 3H), 2.62 (s, 3H), 2.16-2.02 (m, 2H), 2.01-1.92 (m, 2H). MS (ESI) [M+H] ⁺ : 556.3 (ACN: MEOAc).

Example 26:

Scheme 26 shows a synthetic process for making embodiments of formula (I).

Scheme 26

To a stirred solution of N-[(2-methoxy-4-pyridyl)methyl]-N,5-dimethyl-4-(4- piperidyl)thieno[2,3-d]pyrimidine-6-carboxamide (70 mg, 0.17 mmol) in MeCN (14 mL) was added K2CO3 (0.01 mL, 0.51 mmol), followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.05 mL, 0.34 mmol) drop-wise at ambient temperature. The reaction was sealed and allowed to stir at 60 °C temperature for 16 hr. After completion, the reaction was concentrated to dryness and the residue was taken up in EtOAc (20 ml). The organic layer was washed with water (2 x 10 ml), followed by saturated brine solution (1 x 10ml). The organics were then separated, dried over anhydrous NaiSCL, filtered and concentrated to dryness. The crude product was then purified by prep HPLC to afford N-((2-methoxypyridin-4-yl)methyl)-N, 5-dimethyl -4-(l-(2, 2, 2- trifluoroethyl)piperidin-4-yl)thieno[2,3-d]pyrimidine-6-carb oxamide (4.4 mg, 0.0088 mmol, 5.2% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) d 8.98 (s, 1H), 8.15 (s, 1H), 6.88 (s, 1H), 6.67 (s, 1H), 4.65 (s, 2H), 3.89 (s, 3H), 3.55-3.47 (m, 1H), 3.27- 3.14 (m, 2H), 3.14-3.01 (m, 2H), 2.99 (s, 3H), 2.70-2.53 (m, 5H), 2.13-1.97 (m, 2H), 1.86-1.77 (m, 2H). MS (ESI) [M+H] ⁺ : 493.8 (ACN: HCOOH).

Example 27: Androgen receptor inhibition

Compounds of the invention were tested for inhibition of androgen receptor transcriptional activity. 22Rvl cells stably expressing the Cignal AR reporter were generated according to the Qiagen Cignal reporter protocol. These cells are seeded in RPMI + 10% charcoal- stripped serum at 20k cells/well in 384 well format (Corning 3570). The next day, cells are induced with R1881 to a final concentration of 1 nM and treated with compounds in half-log, lOpt dose from top concentration 10 mM. All dispenses are performed from lOOOx DMSO stock via the Echo 525 liquid handler. Final assay volume is 50 pL with 0.2% DMSO. 24 hours from treatment, the OneGlo assay is performed according to the Promega protocol. The plate is read using the Envision plate reader.

The test data shows that the compounds disclosed herein are effective as AR inhibitors and would be suitable candidates for therapy relating to AR-mediated disorders. Results appear in the following Table.

Potency grades A, B, or C in the Table were assigned to each compound based on the test date as follows:

• A = 1 - 200 nM

· B = 201 - 1000 nM

• C = 1001 - 9999 nM

Table: Compounds and potency grades

The contents of all references, pending patent applications, and published patents cited throughout this disclosure are hereby expressly incorporated by reference.

The foregoing embodiments are presented by way of example only. A person of ordinary skill in relevant fields would understand that various modifications may be made without deviating from the spirit and scope of the present invention.