FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10, rule 13)
AKT INHIBITORS"
ELI LILLY AND COMPANY, a corporation of the State of
Indiana, United States of America, having a principal place
of business at Lilly Corporate Center, City of Indianapolis,
State of Indiana 46285, United States of America
The following specification particularly describes the invention and the manner in which it is to be performed.

AKT INHIBITORS
The phosphotidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway encompasses a number of signaling points which are critical in the control of cell growth and survival. AKT, also known as protein kinase B, is a serine-threonine protein kinase which has a key role in this pathway. Activation of AKT is mediated by PI3K. PI3K generates phospholipids which bind to AKT. Upon binding, AKT is recruited to the plasma membrane and is activated through phosphorylation. AKT activation and signaling promotes cell survival, growth and proliferation. Increased AKT activation has been implicated in a wide variety of cancers.
A series of substituted piperidine compounds having AKT inhibitory activity arc disclosed in WO 2008/075109. These compounds are disclosed for use in the treatment of diseases or conditions comprising or arising from abnormal cell growth or abnormally arrested cell death, including cancer.
There remains a need to provide alternative AKT inhibitors which can be used in the treatment of proliferative disorders such as cancer. The present invention provides alternative AKT inhibitors. Certain compounds of the present invention are more potent AKT inhibitors than those known in the art.
Certain compounds of the present invention have low kinase 2 (ROCK2) activity compared to inhibitors known in the art. Certain compounds of the present invention have improved oral efficacy compared to AKT inhibitors known in the art.
The present invention provides compounds of the formula:
Formula I
Y N


wherein: A is
R' F /
R1 isCH3, CH2CH3orCF3;
R2 is H, CF3, CH2CF3, CH2CH2CF3, C1-C4alkyl, C3-C6cycloalkyl, CN, CI, Br, CH=CH2, CH2CH2OCH3, C(CH3)2CH2OCH3 or tetrahydropyran-4-yl, wherein C3-C6 cycloalkyl is optionally substituted by methyl at the 1-position and tetrahydropyran-4-yl is optionally substituted with methyl at the 4-position, and R3 is H; or R2 and R3 are both CI; and R4 is H and R5 is CH3, C(CH3)3, CH(CH3)2, cyclobutyl, cyclopentyl, CH2-cyclopropyl. C(CII3)2CH2CH3 or tetrahydropyran-4-yl; or R4 and R5 are both CH3; or R4 and R5 together with the N to which they are attached form a pyrrolidine, optionally substituted by hydroxy at the 3-position, or an azetidine; or a pharmaceutically acceptable salt thereof.
The present invention provides a pharmaceutical formulation comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.
The present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in therapy.
The present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in treatment of lung cancer, breast cancer or glioblastoma. This invention further provides a method of treating lung cancer, breast cancer or glioblastoma in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. Additionally, this invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of lung cancer, breast cancer or glioblastoma. Furthermore, this invention provides a pharmaceutical composition for use

in therapy comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and provides a pharmaceutical composition for treating lung cancer, breast cancer or glioblastoma comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof.
The present invention provides a pharmaceutical composition comprising a compound of the present invention together with a pharmaceutically acceptable carrier and optionally other therapeutic agents.
The general chemical terms used in the formulae above have their usual meanings. For example, the term "01-04 alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of one to four carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl. Ethyl, propyl, isopropyl. butyl and isobutyl are preferred alkyl groups. Ethyl is particularly preferred.
Compounds of this invention are bases, and accordingly react with any of a number of organic and inorganic acids to form pharmaceutically acceptable salts and the present invention includes the pharmaceutically acceptable salts of the compounds of Formula I. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of Formula I that are substantially non-toxic to living organisms. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977), which are known to the skilled artisan. In one embodiment, the compound of the present invention is the free base or the hydrochloride salt. In particular, it is the free base.
Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastcreomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention. The specific stereoisomers and enantiomers of compounds of Formula I can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen," Stereochemistry of Organic Compounds", (Wiley-Interscience 1994), and

European Patent Application No. EP-A-838448, published April 29, 1998. Examples of resolutions include recrystallization techniques or chiral chromatography.
The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120.
The designation " ""^ " refers to a bond that protrudes forward out of the plane
of the page. The designation" " refers to a bond that protrudes backward out of the
plane of the page.
The term "enantiomeric enrichment" refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ec." which is found using the following equation:
%ee=E'-E2 wherein E is the percentage amount of the first enantiomer and E is the percentage amount of the second enantiomer. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column.
It is preferred that the carbon to which R1 is attached is in the R configuration: R1

n The term "R enantiomer" as used herein means that there is a %ee of the R enantiomer of greater than 90%, preferably greater than 95% and more preferably greater than 98%.

The skilled artisan will also appreciate that compounds of Formula I exist as tautomers, for example:



HO

HO
F F
Although tautomers are structurally distinct, the skilled artisan will appreciate that they exist in equilibrium and are easily and rapidly interconvertible under ordinary conditions. (See, March, Advanced Organic Chemistry, Third Edition, Wiley Interscience, New York, New York (1985), pages 66-70; and Allinger, Organic Chemistry, Second Edition, Worth Publishers, New York, New York, (1976), page 173). As such, the representation of a compound of Formula I in a single tautomeric form contemplates both tautomeric forms individually and mixtures thereof.
The exemplified compounds were named using the naming program within Chcm Draw Ultra version v 10 or Chem Bio Viz Ultra version v 11.
In one embodiment, the present invention comprises compounds of Formula 1 wherein A is:
R1

In particular, A is:

R1

^ H
In one embodiment, R1 is CH3 or CF3. In particular, R1 is CFI3. In an alternative embodiment, the present invention comprises compounds oi" Formula I wherein A is:
H
In one embodiment, the present invention comprises compounds of Formula I wherein R2 is CF3, CH2CF3, CH2CH2CF3, CrC4alkyl, C3-C6cycloalkyl, CN, CI, Br. CH-CH2, CH2CH2OCH3, C(CH3)2CH2OCH3 or tetrahydropyran-4-yl, wherein C3-C6 cycloalkyl is optionally substituted by methyl at the 1-position and tetrahydropyran-4-yl is optionally substituted with methyl at the 4-position, and R3 is H; or R2 and R3 are both CI. In particular, R2 is CF3, CH2CF3, CH2CH2CF3, CH2CH3, (CH2)2CFI3, (CH2)3CII3, CH(CH3)2, CH2CH(CH3)2, C3-C6 cycloalkyl, CI, Br, CH=CH2, CII2CII2OCII3. C(CH3)2CH2OCH3 or tetrahydropyran-4-yl, wherein C3-C6 cycloalkyl is optionally substituted by methyl at the 1-position and tetrahydropyran-4-yl is optionally substituted with methyl at the 4-position, and R3 is H; or R2 and R3 are both CI. More particularly, R2 is CF3, CH2CF3, CH2CH3 or tetrahydropyran-4-yl and R3 is H. Even more particularly, R2 is tetrahydropyran-4-yl and R3 is H.
In another embodiment, the present invention comprises compounds of Formula 1 wherein R2 is CF3, CH2CF3, CH2CH2CF3, CH2CH3, (CH2)2CH3, cyclopropyl, Br, CH2CII2OCFI3 or tetrahydropyran-4-yl, and R3 is H. In particular, R2 is CH2CF3, CH2CH2CF3 or CH2CII3, and R3 is H.
In one embodiment, the present invention comprises compounds of Formula I wherein R4 is H and R5 is CH3, C(CH3)3, CH(CH3)2, cyclobutyl, cyclopentyl or CII2-cyclopropyl; or R4 and R5 are both CH3; or R4 and R5 together with the N to which they are attached form a pyrrolidine, optionally substituted by hydroxy at the 3-position, or an azetidine. In particular, R4 is H and R5 is CH3, C(CH3)3, CH(CH3)2, cyclobutyl,

cyclopentyl or CFb-cyelopropyl; or R4 and R5 together with the N to which they are attached form a pyrrolidine or an azetidine. More particularly. R and R together with the N to which they are attached form a pyrrolidine.
In another embodiment, the present invention comprises compounds of Formula I wherein R4 is H and R5 is C(CH3)3; or R4 and R5 together with the N to which they arc attached form a pyrrolidine or an azetidine. In particular, R4 and R3 together with the N to which they are attached form a pyrrolidine or azetidine.
In a further embodiment, the present invention comprises compounds of Formula I wherein: A is
H or H ;
Rl is CH3 or CF3;
R2 is CF3, CH2CF3, CH2CH2CF3, CH2CH3, (CH2)2CH3, (CH2)3CH3, CH(CH3)2, CH2CH(CH3)2, C3-C6cycloalkyl, CI, Br, CH-CH2, CH2CH2OCH3, C(CH3)2CH2OCIl3 or
tetrahydropyran-4-yl, wherein C3-C6cycloalkyl is optionally substituted by methyl at the 1-position and tetrahydropyran-4-yl is optionally substituted with methyl at the 4-position, and R3 is H; or R2 and R3 are both CI; and
R4 is H and R5 is CH3, C(CH3)3, CH(CH3)2, cyclobutyl, cyclopentyl or CH2-cyclopropyl; or R4 and R5 together with the N to which they are attached form a pyrrolidine or an azetidine; or a pharmaceutieally acceptable salt thereof.
In yet a further embodiment, the present invention comprises compounds of the formula:

Formula II wherein:
R2 is CF3, CH2CF3, CH2CH3 ortetrahydropyran-4-yI; or pharmaceutically acceptable salts thereof.
In another embodiment, the present invention comprises compounds of Formula 1
wherein:
R1

A is
R1 isCH3, CF3orCH2CH3;
R2 is CF3, CH2CF3, CH2CH2CF3, CH2CH3, (CH2)2CH3, cyclopropyl, Br, CI I2CH2OCH3 or tetrahydropyran-4-yl, and R3 is H;
R4 is H and R5 is C(CH3)3; or R4 and R5 together with the N to which they arc attached form a pyrrolidine or an azetidine; or a pharmaceutically acceptable salt thereof
In yet another embodiment, the present invention comprises compounds of the formula:


H Formula III
wherein:
R1 isCH3orCF3;
R2 is CH2CF3, CH2CH2CF3 or CH2CH3;
R and R together with the N to which they are attached form a pyrrolidine or an azetidine; or a pharmaceutically acceptable salt thereof.
In another embodiment, there is provided the following compounds, or pharmaceutically acceptable salts thereof:
(R)-5-methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(333-trifluoropropyl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one; (R)-4-(4-(4-ethyl-l-(2-(pyrro^ 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one; and
(R)-4-(4-( 1 -(2-(azetidin-1 -yl)ethyl)-4-(2,2,2-triflouroethyl)-1 H-imidazol-2-yl)piperidin-1 yl)-5-(triflouromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-onc.
In an embodiment, the compound of the present invention is (R)-5-methyl-4-(4-(1 -(2-(pyrrolidin-1 -yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-yl)pi peri din-1 -yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one, or a pharmaceutically acceptable salt thereof. In particular, the compound is (R)-5-methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one. More particularly, the compound is (R)-5-Methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one crystalline form III. (R)-5-Methyl-4-(4-(l-

(2-(pyrrolidin-1 -yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-yl)piperidin-1 -yl )-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one crystalline form III is characterised by an X-ray powder diffraction pattern (CuKoc radiation, X = 1.54056 A) comprising a peak at 8.53 (29 ± 0.1°) and optionally one or more peaks selected from 17.06, 7.97 and 14.17 (20 ± 0.1 °). Preferably, characterised by an X-ray powder diffraction pattern comprising peaks at 8.53, 17.06, 7.97 and 14.17 (29 ± 0.1°).
The compounds of the present invention are inhibitors of AKT and arc therefore useful in the treatment of cancer. In particular, the treatment of cancers in which the PI3K/AKT/mTOR pathway is activated, including breast cancer (Carpten et al, 448: 439-444 (2007)), in particular, HER2 positive breast cancer (Yakes et al, Cancer Research, 62: 4132-4141 (2003)); colorectal cancer (Parsons et al., Nature, 436: 792 (2005); Carpten et al., 448: 439-444 (2007)); ovarian cancer (Carpten et al., 448: 439-444 (2007)); lung cancer, in particular, squamous cell lung carcinoma (Malanga et al.. Cell Cycle, 7:5: 665-669 (2008)); gastric carcinoma (Byun et al., Int. J. Cancer, 104: 318-327 (2003)); pancreatic cancer (Ruggeri et al, Molecular Carcinogenesis, 21: 81-86 (1998)): head and neck squamous cell carcinoma (Pedrero et al., Int. J. Cancer, 114: 242-248 (2005)); melanoma (Stahl et al., Cancer Research, 64: 7002-7010 (2004)); glioblastoma (The Cancer Genome Atlas Research Network, 455: 1061-1068 (2008)); prostate cancer (Sasaki et ah, Biochem. Biophys. Res. Comm., 399(1): 79-83 (2010)); bladder cancer (Ching et al., Lab. Invest., Epub. 26 July 2010); mesothelioma (Mohiuddin et al.. Annals of Sur. Oncol., 9(3): 310-316 (2002)); sarcoma, in particular soft tissue sarcoma (Zhu et al, Cancer Res., 68(8): 2895-2903 (2008)); and renal cancer (Hara et al, Annals of Oncol, 16: 928-933 (2005)).
The compounds of the present invention, or pharmaceutic ally acceptable salts thereof, can be used in a method of treating cancer, in particular, the cancers described above, in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. Further provided are the compounds of the present invention, or pharmaceutically acceptable salts thereof, for use in the treatment of cancer, in particular. the cancers described above. Furthermore, the compounds of the present invention, or pharmaceutically acceptable salts thereof, can be used in the manufacture of a medicament for the treatment of cancer, in particular, the cancers described above. There

is also provided a pharmaceutical composition for treating cancer, in particular, the cancers described above, comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof.
The compounds of the present invention may be used in combination with other therapeutic agents and in particular, mTOR (mammalian target of rapamycin) inhibitors, EGFR (epidermal growth factor receptor) inhibitors, gemcitabine (Gemzar®), cisplatin. tasisulam (sodium N-[(5-bromothiophen-2-yl)sulfonyl]-2,4-dichlorobenzamidc). pemetrexed (Alimta®), docetaxel (Taxotere®), doxorubicin (Doxil®), irinotccan (Campto®; Camptosar®), paclitaxel (Taxol®) or tamoxifen. Preferred mTOR inhibitors include rapamycin (also known as sirolimus) and analogues thereof such as cvcrolimus (42-0-(2-hydroxy)ethyl-rapamycin; disclosed in EP 1 413 581), temsirolimus (42-(3-hydroxy-2-(hydroxymethyl)-2-methyl propanoate)-rapamycin; Torisel®; disclosed in WO 95/28406) and deforolimus (42-(dimethylphosphinate)rapamycin; disclosed in WO 03/64383). Preferred EGFR inhibitors include erlotinib (Tarceva®), cetuximab (Erbitux®; disclosed in EP 0 359 282), panitumumab (Vectibix®; disclosed in EP 0 359 282) and gefinitib (Iressa®; disclosed in EP 0 566 226).
In one embodiment, the present invention provides a product containing a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a therapeutic agent selected from those listed above as a combined preparation for simultaneous, separate or sequential use in therapy. The present invention further provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in simultaneous, separate and sequential combination with a therapeutic agent selected from those listed above in the treatment of breast cancer, colorectal cancer. ovarian cancer, lung cancer, gastric carcinoma, pancreatic cancer, head and neck squamous cell carcinoma, melanoma, glioblastoma, prostate cancer, bladder cancer, mesothelioma, sarcoma and renal cancer. The present invention further provides a method of treating a cancer selected from the group consisting of breast cancer, colorectal cancer. ovarian cancer, lung cancer, gastric carcinoma, pancreatic cancer, head and neck squamous cell carcinoma, melanoma, glioblastoma, prostate cancer, bladder cancer, mesothelioma, sarcoma and renal cancer comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable salt

thereof, and a therapeutic agent selected from those listed above in amounts that in combination are effective.
In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention together with a pharmaceutically acceptable carrier and optionally other therapeutic agents. In particular, a therapeutic agent selected from those listed above.
Oral administration of the compounds of the present invention is preferred. Depending on the circumstances, other routes of administration, for example intravenous, may be used or even preferred. Transdermal administration may be very desirable for patients who are forgetful or petulant about taking oral medicine. Compounds of the present invention may also be administered by the percutaneous, intramuscular, intranasal or intrarectal route in particular circumstances. The route of administration may be varied in any way, limited by the physical properties of the drugs, the convenience of the patient and the caregiver, and other relevant circumstances (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).
The compounds of Formula I can be prepared by one of ordinary skill in the art following art recognized techniques and procedures. More specifically, compounds of Formula I can be prepared as set forth in the schemes, preparations, and examples set forth below. It will be recognized by one of skill in the art that the individual steps in the following schemes may be varied to provide the compounds of Formula I. The reagents and starting materials are readily available to one of ordinary skill in the art. All substituents, unless otherwise specified, are as previously defined.
Scheme 1



Formula I

In Scheme 1, a compound of Formula I may be prepared by a nuclcophiiic substitution reaction between the amine group of the piperidine ring of compound (1) and the leaving group, chloro group of compound (2). Compound (1) and compound (2) arc dissolved in suitable solvent such as N-methylpyrrolidinone, methanol or n-propanol with an appropriate base such as diisopropylethylamine, triethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene. The reaction may be heated in a flask or in a microwave tube. A compound of Formula I may be isolated by methods known in the art such as an aqueous workup which may include an acid wash with aqueous phosphoric acid followed by an aqueous base wash with aqueous sodium hydroxide and further purification such as silica gel chromatography or high pressure liquid chromatography (HPLC-Chiral AD). Alternatively, after the aqueous workup, a compound of Formula I may be isolated by recrystallization from a solvent such as a 75% mixture of methyl tert-butyl ether and hexanes.
A salt of a compound of Formula I may be prepared by dissolving a compound oi" Formula I in an appropriate aqueous acid such as 4M hydrochloric acid and may be isolated by concentration under reduced pressure. Alternatively, acidic reverse phase chromatography of a compound of Formula I may be used to provide the dihydrochloride or trifluoroacetate salt.
Scheme 2


Formula I

In Scheme 2, an alternative route is described for the preparation of a compound of Formula I (A is defined previously). This synthetic route involves an amine substitution reaction between compound (16) and an appropriate amine to give the -NR4R5 substituent defined for a compound of Formula I. Compound (16) is dissolved in an appropriate solvent such as dimethylformamide or dimethyl sulfoxide. A suitable base such as triethylamine is added. An appropriate amine that will result in the -NR4R? substituent defined for a compound of Formula I is added. The reaction is heated at around 50°C until completion of the reaction. A compound of Formula I is isolated by traditional means such as an aqueous work-up, concentration, and chromatography of the organic extracts.
Compound (16) is prepared by dissolving compound (17) in an appropriate solvent such as dichloromethane, adding an appropriate base such as triethylamine and cooling to around 0°C. Methanesulfonyl chloride is added dropwise. Afterwards the reaction is quenched with saturated aqueous sodium bicarbonate followed by the traditional methods known in the art to isolate compound (16). Compound (16) may be used without purification to prepare a compound of Formula I. Compound (17) may be prepared from compound (18) (n= 1 to 2) and compound (2) by methods described in Scheme 1. Compound (17) may be used without purification to prepare compound (16).
If the resulting compound of Formula I is a racemate, it may be separated into the individual enantiomers by methods known in the art such as chiral chromatography.

The chiral purity of the individual enantiomers of a compound of Formula I can be determined by comparing the two enantiomers by HPLC (Chiralpak AD-H) and superfluid chromatography (Chiral AD-H).
Scheme 3

In Scheme 3, compound (2b) and (2c), enantiomers of the racemic mixture of compound (2a), 4-chloro-5-RI-6,8-dihydro-5H-pyrido[2,3-d]pyrimidin-7-one, may be prepared by a series of reactions beginning with compound (5) and compound (6). Compound (2a) is prepared by combining compound (3) with aqueous ammonium hydroxide (20-30%) or a solution of ammonia gas in isopropanol with heating. Compound (2a) can be isolated by filtration after cooling and a subsequent wash with cold water. Further resolution of compound (2a) by chiral chromatography affords compound (2b) and compound (2c). Compound (2a), (2b) or (2c) may be used by following the synthetic pathway in Scheme 1 or Scheme 2 to form the racemate of a compound of Formula I or the individual enantiomers.
Alternatively, compound (2a) may be protected by a nitrogen protecting group such as a tert-butoxycarbonyl (BOC) moiety using terr-butoxycarbonyl tert-butyl carbonate and 4-(dimethylamino)pyridine in a solvent such as dichloromethane. Subsequent separation of the racemate by chiral chromatography affords the nitrogen BOC-protected compounds (2b) and (2c). Deprotection by methods known in the art

such as reacting the BOC-protected compound (2b, 2c) with hydrochloric acid in dioxanc affords the desired single enantiomer.
Compound (3) may be prepared by a halogen substitution reaction of compound (4). Compound (3) is dissolved in suitable solvent such as acetonitrile or toluene, in the presence of a base such as N,N-diethylaniline and a chlorinating reagent such as phosphoryl chloride. After refluxing the reaction mixture, compound (3) may be isolated by traditional means such as an aqueous workup with 3M aqueous solution of potassium phosphate dibasic, extraction with an appropriate solvent such as methyl tert-butyl ether, washing of the organic layer with water and concentration in vacuo.
Alternatively, compound (2a) may be synthesized to include a nitrogen protecting group such as a 2,4-dimethoxybenzyl group. Compound (3) is first dissolved in a suitable solvent such as dimethylformamide. A base such as diisopropylethylamine and the reagent 2,4-dimethoxybenzylamine are added. The 2,4-dimethoxybenzyl intermediate is isolated by methods known in the art such as an aqueous work-up. This intermediate is subjected to heating in the presence of a base such as diisopropylethylamine to form a 2,4 dimethoxybenzyl protected compound (3). This compound may be carried on in the synthesis of Scheme 1 to form a 2,4-dimethoxybenzyl protected compound of Formula I. A 2,4-dimethoxybenzyl protected compound of Formula I is deprotectcd by traditional means to afford the racemate and followed by chiral chromatography to separate the individual enantiomers.
Compound (4) may be prepared by a Michael addition reaction followed by an in situ ring formation reaction. Propanedioic acid dimethyl ester (compound (5)) and compound (6) are added to a mixture of sodium methoxide in methanol solution and formamidine acetate. Compound (4) may be isolated by traditional means by adjusting the pH of the reaction to around 3, filtering, and washing the product with a cooled solvent mixture such as methanol/water.
Scheme 4
F
?' 9 C! CI ci F-4-F
M^AH H2NCH2CF3 X ^CH2CF3 V' F T T'
Nn2 ^N NH2 ^N^N^O
(7) (8) (9) (2d) H

In Scheme 4, compound (2d) may be prepared by a series of reactions beginning with a reductive amination reaction between commercially available starting materials such as the amine (10), 2,2,2-trifluoroethylamine, and a commercially available aldehyde, 4-amino-6-chloropyrimidine-5-carbaldehyde (7), to form the imine (8) in a solvent mixture such as tetrahydrofuran and methanol in the presence of titanium tetraisopropoxide. The imine is reduced by dissolving compound (8) in a solvent such as dichloromethane, cooling under nitrogen, adding methanesulfonic acid and a suitable reducing agent such as borane tert'-butylamine. The amine (9) is isolated by a basic aqueous work-up and drying the organics in vacuo. Compound (9) may be used directly in the next reaction without further purification. Compound (2d) is prepared by reacting compound (9) with triphosgene in the presence of a base such as triethylamine in an appropriate solvent such as dichloromethane with cooling to around 0°C under nitrogen and with subsequent overnight heating of the reaction mixture to around 40°C. Compound (2d) is isolated by methods known in the art such as an aqueous work-up, concentration, and chromatography of the organic extracts. A compound of Formula I can be realized by utilizing compound (2d) as in Scheme 1 and 2.
Scheme 5

(15a) R4 and R5 form a pyrrolidine

OMs is a methylsulfonyloxy group

In Scheme 5, compound (1) may be prepared by deprotection of a corresponding tert-butoxycarbonyl compound (15) by traditional means such as adding to compound (15), which is optionally dissolved in a suitable solvent such as dichloromethane. methanol or isopropanol, hydrogen chloride in dioxane, isopropanol, methanol or ethanol. The reaction may be performed at temperatures ranging from room temperature to around 50°C for about 2 hours to 18 hours. Traditional workup may include evaporating the volatiles followed by an optional basification step with a base such as 2M aqueous sodium hydroxide, extraction with a solvent such as ethyl acetate, and concentration in vacuo to give a compound (1) as the free base, n HC1 or n acetate salt.
Compound (15) may be prepared from compound (14) by the same reaction described in Scheme 2 for the preparation of the compound of Formula I from compound (16).
Compound (14) may be prepared from compound (13) by the same reaction described in Scheme 2 for the preparation of compound (16), from compound (17).

Compound (13) may be prepared by an acid catalyzed deprotection reaction from compound (12) according to the synthetic Path A. Compound (12) is dissolved in suitable solvent such as tetrahydrofuran. An acid catalyst such as aqueous IN hydrochloric acid is added. Compound (13) can be isolated by methods known in the art such as an aqueous workup.
Compound (12) is drawn as one regioisomer but may also represent the mixture of regioisomers. The synthesis and isolation of the regioisomers (12a) and (12b) are shown in Scheme 6. Compound (12) may be prepared by dissolving compound (11) in suitable solvent such as dimethyl sulfoxide with a base such as potassium hydroxide or potassium tert-butoxide. Sodium iodide may be optionally added. 2-(2-Haloethoxy)telrahydropyran is added to the reaction. The reaction is maintained at room temperature for around 4 hours, or may be heated to around 45°C to 50°C for about 1 hour to 12 hours. Compound (12) may be isolated by methods known in the art such as an aqueous workup, concentration in vacuo and purification by chromatography.
Alternatively Path B may be followed to provide compound (1) wherein R4 and R? together with the N to which they are attached form a pyrrolidine. Compound (15a) may be prepared by reacting compound (11) with l-(2-chloroethyl)-pyrrolidine hydrochloride using the reaction conditions described above in relation to the conversion of compound (11) to compound (12). Compound (15a) is drawn as one regioisomer but may also represent the mixture of regioisomers. The synthesis and isolation of the regioisomers (15b) and (15c) are shown in Scheme 6. The BOC protecting group may be removed by traditional means as described above.
Scheme 6




and
and
(15b)

(12b)

When alkylating compound (11) as in Scheme 5, regioisomers (12a) and (12b) of compound (12) and regioisomers (15b) and (15c) of compound (15a), respectively, may be formed in varying ratios as shown in Scheme 6. In some cases, only the desired isomer (12a) or (15b) is obtained. In other cases, the synthesis results in a ratio which is in favor of the desired compound (12a) or (15b). In this instance, further purification is optional and may occur at a later step to remove the minor impurity. If, however, the ratio between compound (12a) and compound (12b) or compound (15b) and compound (15c) is not as dominant for the desired isomer purification is necessary. Purification to isolate the desired isomer (12a) or (15b) includes column chromatography or recrystallization from an appropriate solvent such as isopropyl alcohol with butanedioic acid, or 1M or 3M hydrochloric acid in methanol or methanol/ethanol mixture with ethyl acetate.

Scheme 7

(12d)R2, R3=halogen (12e) R2=halogen, R3=H
In Scheme 7, the introduction of R and R may be achieved by a halogcnation substitution reaction between compound (12c) and a halogenating agent such as N-bromosuccinimide to provide a dihalo (12d) or monohalo (12e) substituted compound. Compounds (12d) and (12e) may be carried on in the synthesis such as in Scheme 5. Also compound (12d) when R2 and R3 are bromo may be transformed into compound (12e) by reacting the compound with n-butyllithium at a reduced temperature in an appropriate solvent such as tetrahydrofuran followed by the addition of isopropyl alcohol.
Compound (12e) can be subjected to Suzuki coupling reaction conditions such as palladium acetate, tricyclohexylphosphine, tribasic potassium phosphate N-hydrate and a substituted boronic acid. For example, in the case of cyclopropylboronic acid the bromine will be substituted by cyclopropyl.


(11b) R2=R3=ci, (15d) R2=R3=CI,
(11c) R2=CI R3=H (15e) R2=CI R3=H
(11d)R2=R3=l (15f) R2=R3=I
(15g) R2=l R3=H
In Scheme 8, the introduction of R and R , when R and R are chloro or iodo, may be achieved by a halogenation substitution reaction between compound (11a) and a halogenating agent such as N-chlorosuccinimide, N-iodosuccinimide or iodine to provide a dihalo (1 lb or 1 Id) or monohalo (lie) substituted compound under reactions conditions commonly found in the literature. Compound (lib) and (lie) may be isolated from the same reaction mixture by column chromatography. Compound (lid) may be isolated by pouring the reaction mixture over a solution of aqueous sodium bisulfate to form a yellow suspension, filtering and washing the solid. Compound (15d, 15e and 15f) may be prepared by following the synthesis found in Scheme 5 from the corresponding compound (11).
Compound (15f) may be mono-dehalogenated in the presence of isopropylmagnesium chloride and 2-methyltetrahydrofuran to form compound (15g). Compound (15g) can be subjected to Suzuki coupling reaction conditions such as palladium acetate, tri-tert-butylphosphonium tetrafluoroborate and a substituted boronate ester such as 2-(3,6 dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (compound (38) which may be prepared in accordance with Scheme 16) in an appropriate solvent such as dimethylsulfoxide with a base such as sodium carbonate. The resulting 3,6 dihydro-2H-pyran-4-yl substituted compound may be reduced under an atmosphere of hydrogen in the presence of palladium on charcoal in an appropriate solvent such as ethanol to form compound (15) wherein R = tetrahydro-2H-pyran-4-yl.

Scheme 9


N
O
(CH-).CO O
(15h) (151)
In Scheme 9, compound (15h) may be subjected to Suzuki coupling reaction conditions such as combining with the boronate ester 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane, in the presence of a base, typically tribasic potassium phosphate N-hydrate, and a palladium catalyst typically bis(dibenzylideneacetone)palladium(0) or palladium acetate, and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl] phosphanc. The resulting compound (15i) can be carried forward as in Scheme 5 to form compound (1).
Alternatively, this reaction may be performed on the hydroxy-ethyl substituted compound (13) rather than the pyrrolidine-ethyl substituted compound. The resulting alkene compound may be subjected to hydrogenation conditions which include 10% palladium on carbon in an appropriate solvent such as ethanol under a hydrogen atmosphere to form the alkyl substituted compound. The compound may be isolated by filtration through Celite®, a subsequent wash with methanol and concentration in vacuo.
Scheme 10

(CH3)3CO'
(12) In Scheme 10, compound (18) may be prepared by traditional de-protection
methods. Compound (12) is dissolved in a suitable solvent such as methanol, adding 4M

hydrochloric acid in a dioxane solution and stirring overnight. Compound (18) can be isolated by methods known in the art such as concentrating in vacuo to give compound (18) as a nHCl salt. Compound (18) may be utilized in Scheme 2 to form a compound of Formula I.
Scheme 11

In Scheme 11, compound (lie) may be prepared by a two step process which includes an oxidation reaction of a ketone (22) or aldehyde (26) to compound (23) and a condensation reaction between ammonia, compound (23) and the aldehyde moiety of compound (24). Selenium dioxide is combined in a suitable solvent mixture such as 1,4-dioxane and water with an acid such as acetic acid. The ketone (22) or the aldehyde (26) is added to the oxidizing agent, heated to around 90 °C, stirred about 2 to 18 hours, and filtered to obtain the compound (23). An optional work-up might include filtering through Celite®, concentrating in vacuo and dissolving the residue in a solvent such as methanol. Compound (24) is dissolved in methanol with ammonium hydroxide or ammonium acetate and optionally cooled to around 0°C. The compound (23) is added dropwise and the reaction is stirred overnight. Compound (He) can be isolated by methods known in the art such as filtration, an aqueous work-up and purification by silica gel chromatography. An optional work-up might include diluting the residue with methyl tert-butyl ether and water and adjusting the pH to around 2 by adding aqueous phosphoric acid, separating the aqueous layer, washing the aqueous layer with methyl tert-butyl ether, adjusting the pH to around 10 with sodium carbonate and a final extraction with

ethyl acetate. The organic layers are combined, washed with saturated sodium chloride. filtered and concentrated in vacuo to give compound (lie).
Compound (23) may be prepared, if not commercially available, by a series of oxidation reactions starting from compound (25) or (26). 3,3,3-Triacetoxy~3-iodophthalide is dissolved in a suitable solvent such as dichloromethane. Compound (25) is dissolved in the same solvent and added dropwise to the oxidizing reagent. After about 4 hours, compound (26) can be isolated by methods known in the art such as filtration through Celite®, an aqueous workup involving an aqueous wash with sodium thiosulphate and sodium hydroxide, filtration and concentration in vacuo.

In Scheme 12, compound (22) may be prepared by a Weinreb ketone synthesis which involves forming a Weinreb amide followed by reaction with an organometallic nucleophile and hydrolysis to form the desired ketone. The ester (27) is dissolved in an appropriate solvent such as methanol and a base such as sodium hydroxide is added. The acid (28) may be isolated by traditional means such as an aqueous work-up with methyl tert-butyl ether and an acid wash with aqueous hydrochloric acid. The solid may be carried on in the next reaction without purification. The Weinreb amide (29) is prepared by stirring the acid (28) in an appropriate solvent such as dichloromethane in the presence of l,l'-carbonyldiimidazole and adding N, O-dimethylhydroxylamine hydrochloride. The Weinreb amide is isolated by an aqueous work-up involving washing with aqueous ammonium chloride and saturated aqueous sodium chloride, and concentration in vacuo. Compound (29) may be used in the next step without further purification. The next step involves dissolving the Weinreb amide in a solvent such as tetrahydrofuran, cooling to around 0°C and adding the organometallic nucleophile, methyl magnesium chloride. This complex is hydrolyzed by pouring the reaction mixture into an ice/water mixture or aqueous ammonium chloride. An aqueous work-up involving methyl tert-butyl ether and
j

concentration in vacuo provides compound (22). Compound (22) may be utilized in the next step without purification or after purification by silica gel chromatography.
An alternative approach to compound (22) involves reacting compound (27) with isopropylmagnesium chloride andN, -O-dimethylhydroxylamine hydrochloride in a solvent such as tetrahydrofuran at a reduced temperature to form the Weinreb amide.
Scheme 13

H_0
O
2
Br

N
X Br
R
0"^OC(CH3)3 ~N
(CH3)3CO O
(24) (30)
(11e)
In Scheme 13, compound (1 le) may also be prepared by reacting compound (30) with sodium acetate in water at an elevated temperature, then with compound (24) in an appropriate solvent such as methanol and aqueous ammonium hydroxide. Compound (lie) can be isolated by methods known in the art such as an aqueous workup and may be utilized without further purification.
Scheme 14

(31) (32) (30)
In Scheme 14, the preparation of compound (30) begins with the anion formation of 1,1-dibromomethane (32). The formation of the anion involves the preparation of lithium diisopropylamide from diisopropylamine and n-butyl lithium by methods commonly found in the literature. After formation of lithium diisopropylamide, compound (31) and compound (32) are stirred in an appropriate solvent such as tetrahydrofuran at a reduced temperature and lithium diisopropylamide is added dropwisc while maintaining the reduced temperature. The reaction is quenched with aqueous

hydrochloride acid followed by an aqueous work-up with solvents such as methyl tert-butyl ether and heptane.
Scheme 15

In Scheme 15, the synthesis of compound (1 If) is shown as beginning from the anhydride (33). The synthesis is accomplished by forming (E)-(dimethylhydrazono)-1,1 ,l-trifluoro-propan-2-one by reacting N-methyl-N-(methyleneamino)-methanamine with a base such as 2,6-lutidine and adding trifluoroacetic anhydride at a reduced temperature. The intermediate is reacted with compound (24) in acetic acid and ammonium acetate to form compound (1 If). Compound (1 If) can be further transformed into compound (1 lg) by transforming the trifluoromethyl substitute into a cyano substitute by heating compound (1 If) in ammonium hydroxide, cooling and filtering to isolate the solids.
Scheme 16

(36)
In Scheme 16, compound (38) can be prepared through a series of reactions beginning with a Williamson ether synthesis between compound (34) and (35) in the presence of a base such as sodium hydride and a solvent such as methyl tert-b\x\y\ ether to form the ether (36). Compound (36) is subjected to standard reaction conditions to form the boronate ester (37). These reagents may include lithium chloride, cuprous monochloride and bis(pinacolato)diboron and a suitable solvent such as

dimethyformamide. Compound (38) may be prepared by a ruthenium catalyzed olefin metathesis utilizing the 2nd generation Grubbs' catalyst in an appropriate solvent such as dichloromethane. Compound (38) may be utilized in the synthesis of a compound of Formula I as described in Scheme 8.
The skilled artisan will appreciate that not all of the substituents in the compounds of Formula I will tolerate certain reaction conditions employed to synthesize the compounds. These moieties may be introduced at a convenient point in the synthesis, or may be protected and then de-protected as necessary or desired. The skilled artisan will also appreciate that the protecting groups may be removed at any convenient point in the synthesis of the compounds of the present invention. Methods for introducing and removing nitrogen protecting groups are well known in the art; see, for example, Greene and Wuts, "Protective Groups in Organic Synthesis", 3r Ed., John Wiley and Sons, New York, Chapter 7 (1999). Furthermore, the skilled artisan will appreciate than in many circumstances, the order in which moieties are introduced is not critical. The particular order of steps required to produce the compounds of Formula I is dependent upon the particular compound being synthesized, the starting compound and the relative liability of the substituted intermediates and products.
Preparation 1 (E,Z)-6-Chloro-5-((2,2,2-trifluoroethylimino)methyl)pyrimidin-4-aminc
CI
I X F F
N NH2
Add a solution of 4-amino-6-chloropyrimidine-5-carbaldehyde (0.31 g, 1.94 mmol) in tetrahydrofuran (4 mL) to a mixture of titaniumtetra(isopropoxidc) (0.85 mL. 1.5 eq), 2,2,2-trifluoroethylamine (0.76 mL, 4.9 eq), and methanol (3.8 mL). Stir the reaction at room temperature overnight. Add 2:1 ammonium hydroxide:watcr to the reaction mixture, then dilute with ethyl acetate. Separate the layers. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a white solid (0.44 g, 96%). MS (ES) m/z - 239 [M]+.
Preparation 2

6-Chloro-5-((2,2,2-trifluoroethylamino)mcthyl)pyrimidin-4-amine
CI

Combine (H,Z)-6-chloro-5-((2,2,24rifluoroethylimino)methyl)pyrimidin-4-amine (3.42 g, 14.35 mmol) and dichloromethane (34.8 mL). Cool to 0°C under nitrogen. Add methanesulfonic acid (2.30 mL, 2.4 eq) dropwise via syringe, maintaining the temperature below 5°C. Add a solution of borane tert-butylamine complex (1.86 g, 1.5 eq) in dichloromethane (10 mL) dropwise via syringe, maintaining the temperature below 5°C. Stir the reaction mixture for 1 hour at 0°C. Add 2:1 ammonium hydroxide:water, then dilute with dichloromethane. Separate the layers. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a yellow solid (2.39 g, 69%). MS (ES) m/z = 241 [M]+.
Preparation 3 5-Chloro-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(lH)-onc

Combine 6-chloro-5-((2,2,2-trifluoroethylamino)methyl)pyrimidin-4-amine (9.57 g, 39.78 mmol), triethylamine (5.50 mL, 2.0 eq), and dichloromethane (795 mL). Cool to 0°C under nitrogen. Add a solution of triphosgene (11.85 g, 1.0 eq) in dichloromethane (228 mL). Stir at 0°C for 30 min, and allow to warm to room temperature. Heat the reaction mixture to 40°C overnight. Add aqueous sodium bicarbonate and extract with ethyl acetate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with 9:1 dichloromethanc:methanol. to give the title compound (4.50 g, 42%). *H NMR (400 MHz, DMSO-d6) 5 10.83 (s. 1H), 8.41 (s, 1H), 4.20 (m, 2H), 3.25 (s, 2H).
Preparation 4

Methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate
-CH,

N OH
Add sodium methoxide (14.69 g, 0.85 eq) to methanol (70 mL). Heat to reflux over 15 minutes while adding a mixture of propanedioic acid dimethyl ester (36.64 mL. 320.00 mmol) and methyl crotonate (34.01 mL, 1.0 eq). Reflux the mixture for 40 minutes, then allow the mixture to cool to room temperature. Add a mixture of sodium methoxide (19.02 g, 1.1 eq), methanol (70 mL) and formamidine acetate (39.98 g, 1.2 eq). Stir at room temperature overnight. Cool the mixture in an ice bath and add 5 M aqueous hydrochloric acid, adjusting the pH to 3. Filter to give the title compound (41.00 g. 60%). MS(ES)m/z = 213 [Mf.
Prepare the following compounds essentially as described for methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate:

Prep Compound Name MS (ES) m/z\M\k
5 methyl 3-(4,6-dihydroxypyrimidin-5-yl)pentanoate 227
6 methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4,4-trifluorobutanoate 267
Preparation 7 Methyl 3-(4,6-dichloropyrimidin-5-yl)butanoatc
•CH,

Add methyl 3-(4,6-dihydroxypyrimidin-5-yl)butanoate (41.00 g, 193.21 mmol) to acetonitrile (95 mL). Add phosphoryl chloride (39.50 mL, 2.2 eq) dropwise over ten minutes (exotherm evident). Stir the mixture for ten minutes and add N,N-diethylanilinc (34.00 mL, 1.1 eq) dropwise over ten minutes (exotherm evident). Heat the mixture at

reflux overnight. Cool the mixture in an ice bath. Add slowly to a pre-cooled mixture of potassium phosphate dibasic aqueous solution (336.52 g in 500 mL water, 10 eq). Extract the aqueous layer with ethy! acetate. Wash the organies with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with 10% ethyl acetate in hexanes to 40% ethyl acetate in hexanes, to give the title compound (44.00 g, 55%). MS (ES) m/z = 249 [MJ1.
Prepare the following compounds essentially as described for methyl 3-(4.6-
diehloropyrimidin-5-yl)butanoate:

Prep Compound Name MS (ES) m/z [M]+
8 methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoate 304
9 methyl 3-(4,6-dichloropyrimidin-5-yl)pentanoate 263
10
Preparation 10 (R)-4-Chloro-5-ethyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8M)-one

Dissolve methyl 3-(4,6-diehloropyrimidin-5-yl)pentanoate (10.00 g, 38.01 mmol) in 28% ammonium hydroxide in water (95 mL) and seal in a 350 mL tube. Heat the reaction mixture to 200°C for 2 hours. Cool the reaction mixture in an ice bath, then filter and wash with cold water. Dry the solids under vacuum to give the raeemate. Chiral separation (Chiralpak AS-H, 100% ethanol w/ 0.2 % dimethyl ethylamine) provides the title compound as enantiomer 2 (3.19 g, 40%) (>99 % ee). MS (ES) m/z = 212 |M|Prepare the following compounds essentially as described for (R)-4-chloro-5-
ethyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one:

Prep Compound Name MS (ES) m/z [M]+ Chiral separation
11 (R)-4-chloro-5-(trifluoromethyI)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one 252 Enantiomer 2
>99% ee 100% ethanol

0.2% DME A Chrialpak AS-H
Preparations 12 and 13 4-Chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one
and (R)-4-Chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-onc



and

Add methyl 3-(4,6-dichloropyrimidin-5-yl)butanoate (24.00 g, 96.35 mmol) to 30% aqueous ammonium hydroxide (100.00 mL, 7.5 eq) in a sealed tube. Seal and stir the mixture at 60°C overnight. Cool the mixture in an ice bath. Filter the solid and wash with cold water to give 4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8II)-one (11.35 g, 60%). MS(ES)m/z= 198 [M]+.
Chiral separation (Chiralpak AS, ethanol with 0.2% dimethylethylamine) provides (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as enantiomcr 2 (4.20 g. >99% ee). MS (ES) m/z = 198 [M]+.
Preparation 14 4-Chloro-8-(2,4-dimethoxybenzyl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3'
d]pyrimidin-7(8H)-one


Combine methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoatc (0.71 g. 1.98 mmol) diisopropylethylamine (0.38 mL, 1.1 eq), 2,4-dimethoxybenzylamine (0.32 ml, 1.05 eq), and dimethylformamide (6 mL). Heat at 50°C overnight. Allow to cool to room temperature. Dilute with water and extract with methyl tert-butyl ether. Wash the organic layer with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give a mixture of the title compound and methyl 3-(4-chloro-6-(2,4-dimethoxybenzylamino)pyrimidin-5-yl)-4A4-trifluorobutanoate as an oil. Combine the crude mixture (0.78 g), diisopropylethylamine (0.63 mL), and ethanol (7.8 mL). Heat at reflux for four hours. Allow to cool to room temperature. Filter and rinse with ethanol to obtain the title compound as a white solid (0.43 g, 55%).
Preparation 15 5,5,5-Trifluoropentanal
F
F — —F ^"^
Combine 3,3,3-triacetoxy-3-iodophthalide (17.91 g, 1.2 eq) and dichloromethane (95 mL). Add 5,5,5-trifluoro-l-pentanol (5.00 g, 35.18 mmol) in dichloromethane (238 mL) dropwise under nitrogen. After 4 hours, filter the reaction mixture through Cclitc ®. Concentrate the filtrate in vacuo; combine with 50 mL of dichloromethane and wash with 1:1 10% sodium thiosulphate:aqueous sodium hydroxide (IN). Dry the organics with anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a colorless oil (2.13 g, 43%). 'H NMR (400 MHz, DMSO-d6) 5 9.61 (s, 1H), 2.50 (m. 211), 2.21 (m,2H), 1.66 (m,2H).
Preparation 16 5,5,5-Trifluoro-2-oxopentanal F

Combine 5,5,5-trifluoropentanal (2.01 g, 14.35 mmol), 1,4-dioxanc (10 ml). selenium dioxide (1.62 g, 1.0 eq), water (0.51 mL), and acetic acid (0.69 ml). Heat the mixture at 90°C and stir overnight. Allow the reaction mixture to cool to room temperature. Filter, wash the solids with dioxane. Combine the filtrate and washings to give the title compound (2.21 g, 100%). GCMS m/z = 154.
Prepare the following compounds essentially as described for 5,5,5-trifluoro-2-oxopentanal:

Prep Compound Name MS(ES)#«/zIM]J or [M+18] +
17 2-cyclobutyl-2-oxoacetaldehyde 112
18 2-oxopentanal 119
19 4-methoxy-2-oxobutanal 117
20 4-methoxy-3,3-dimethyl-2-oxobutanal 145
21 4-methyl-2-oxopentanal 115
Preparation 22 1 -Methylcyclobutanecarboxylic acid

CH,0

Add 2.5M n-butyllithium in hexanes (281.91 mL, 2.4 eq) to a solution of diisopropylamine (99.70 mL, 2.4 eq) in tetrahydrofuran (900 mL) at 0°C. Stir for 15 minutes, then add a solution of cyclobutanoic acid (28.65 mL, 293.66 mmol) in tetrahydrofuran (100 mL) dropwise, maintaining the temperature below 5°C. Stir the mixture at 5°C for 5 minutes. Add methyl iodide (18.47 mL, 1.0 eq) dropwise. After 2 days, cool the mixture to 0°C and acidify with 10% aqueous hydrochloric acid. Extract the aqueous phase with ether. Wash the organics with saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to give a yellow oil. Purify by silica gel chromatography, eluting with 5% ethyl acetate in hexanes, to give the title compound as colorless oil (15.77 g, 47%). 'H NMR (400 MHz, CDC13): 8 11.84 (bs, 1H), 2.47 (m, 2H), 1.86 (m, 4H), 1.42 (s, 3H).


Preparation 23

1 -(1 -Methylcyclobutyl)ethanone
C\°
CH3
Add 1.6 M methyl lithium in diethyl ether (176.15 mL, 2.0 eq) dropwise to a solution of 1-methylcyclobutanecarboxylic acid (15.77 g, 138.16 mmol) in diethyl ether (500 mL) at 0°C over 2 hours. Warm the mixture to room temperature and stir for 5 hours. Pour the mixture into ice-cold 3 M aqueous hydrochloric acid. Wash the organics with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a colorless oil (11.70 g, 76% yield). *H NMR (400 MHz, CDCl3-d3): 5 2.38 (m,2H), 1.90 (m,2H), 1.70 (m,2H), 1.38 (s,3H), 1.10 (s,3H).
Prepare the following compounds essentially as described for 1-(1-methylcyclobutyl)ethanone:

Prep Compound Name 'H NMR
24 l-(4-methyltetrahydropyran-4-yl)ethanone 'H NMR (400 MHz,
DMSO-d6):5 3.60(m.
2H), 3.35 (m, 211), 2.12
(s, 3H), 1.85 (m, 211).
1.34 (m,2H), 1.12 (s,
311)
Preparation 25 l-(Tetrahydro-pyran-4-yl)-ethanone -0.

Add butanoic acid, 3-oxo-, methyl ester (18.60 mL, 172.20 mmol), bis(2-chloroethyl)ether (20.20 mL, 1.0 eq), potassium carbonate (52.42 g, 2.2 eq), and sodium iodide (25.88 g, 1.0 eq) in dimethylformamide (861 mL). Heat the reaction mixture at 80°C overnight. Cool to room temperature. Add additional potassium carbonate (23.78 g) and sodium iodide (25.88 g). Heat the reaction mixture at 80°C for two hours, then

^3>^
allow the mixture to cool to room temperature. Filter through Celite ® and wash with ethyl acetate. Wash the filtrate with water and brine. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give methyl 4-acetyltetrahydro-2II-pyran-4-carboxylate (23.06 g).
Combine methyl 4-acetyltetrahydro-2H-pyran-4-carboxylate (23.06 g, 123.84 mmol) with isopropyl alcohol (124 mL) and water (124 mL). Add sulfuric acid (33.00 mL, 5.0 eq). Heat the reaction mixture to 100°C over two nights. Cool and add the reaction mixture slowly to a mixture of sodium bicarbonate (136 g) in water (1 L). Extract with dichloromcthane. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hcxancs to 25% ethyl acetate in hexanes to 50% ethyl acetate in hexanes, to give the title compound (7.39 g, 34%). 'H NMR (400 MHz, DMSO-d6) 5 3.79 (m, 2H), 3.27 (m, 2H), 2.54 (m, 1H), 2.05 (s, 3H), 1.66 (m, 2H), 1.38 (m, 2H).
Preparation 26 tert-Butyl 4-(4-(2,2,2-trifluoroethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate

F F

H3C + CH3 CH3
Combine selenium dioxide (10.45 g, 94.15 mmol), 1,4-dioxane (60 mL), acetic acid (5 mL), and water (5 mL). Heat to 80°C under nitrogen, then slowly add 4,4,4-trifluorobutan-2-one (9.01 mL, 1.0 eq) dropwise. Heat at 90°C under nitrogen for 12 hours, then let cool to room temperature. Filter the reaction mixture to give an orangc-rcd filtrate. To a separate flask, add tert-butyl 4-formylpiperidine-l-carboxylatc (20.08 g, 1.0 eq) in methanol (150 mL) and ammonium hydroxide (117.84 mL, 10.0 cq). Cool to 0°C under nitrogen. Add the filtrate dropwise via addition funnel. Allow to warm to room temperature and stir overnight under nitrogen. Concentrate to dryness in vacuo. Add

water and extract with ethyl acetate. Dry the organics over anhydrous magnesium sulfate. filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 4:1 hexanes:ethyl acetate to 2:1 hexanes:ethyl acetate to 1:1 hcxancs:cthyl acetate to 1:2 hexanes:ethyl acetate to ethyl acetate, to give the title compound as a light brown solid (8.06 g, 26%). MS (ES) m/z = 334 [Mf.
Prepare the following compounds essentially as described for tert-butyl 4-(4-(2,2,2-tritluoroethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate:

Prep Compound Name MS (ES) m/z [M]+
280
27 tert-butyl 4-(4-ethyl-lH-imidazol~2-yl)piperidine-l-carboxylate

28 tert-butyl 4-(4-( 1 -methylcyclobutyl)-1 H~imidazol-2-yl)piperidine-
1-carboxylate 320
29 tert-butyl 4-(4-( 1 -methylcyclopropyl)-1 H-imidazol-2-yl)piperidine-l-carboxylate 306
30 tert-butyl 4-(4-cyclopentyl-1 H~imidazol-2-yl)piperidine-1 -
carboxylate 320
31 tert-butyl 4-(4-isopropyl-1 H-imidazol-2-yl)piperidine-1 -carboxylate 294
32 tert-butyl 4-(4-butyl-1 H-imidazol-2-yl)piperidine-1 -carboxylate 308
33 tert-butyl 4-(4-(4-methyltetrahydro-2H-pyran-4-y 1)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 350 333
34 tert-buty] 4-(4-cyclohexyl-1 H-imidazol-2-yl)piperidine-1 -
carboxylate

Preparation 35 terr-Butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate
N,^ .NH
O O
O

H3C-

CH,

CH.

Combine selenium dioxide (5.72 g, 51.54 mmol), 1,4-dioxane (52 ml), acetic acid (2.4 mL, 0.81 eq), water (2.4 mL), and l-(tetrahydro-pyran-4-yl)-ethanone (6.28 g, 1.0 cq). Stir at 90°C overnight. Cool and filter, then wash with 1,4-dioxane. Add this filtrate to a solution of lerl-butyl 4-formylpiperidine-l-carboxylate (10.47 g, 1.0 eq), methanol (78 mL) and 30% aqueous ammonium hydroxide (30.8 mL) at 0°C. Allow the mixture to warm to room temperature and stir overnight. Concentrate in vacuo and add ethyl acetate and saturated aqueous sodium chloride. Separate the layers. Extract the aqueous layer further with 9:1 dichloromethane:isopropyl alcohol.
Combine selenium dioxide (0.91 g, 8.17 mmol), 1,4-dioxane (8.3 mL), acetic acid (0.4 mL, 0.81 eq), water (0.41 mL), and l-(tetrahydro-pyran-4-yl)-ethanonc (1.00 g, 1.0 eq). Stir at 90°C overnight. Cool and filter, then wash with 1,4-dioxane. Add this filtrate to a solution of tert-butyl 4-formylpiperidine-l-carboxylate (1.66 g, 1.0 eq), methanol (12.4 mL) and 30% aqueous ammonium hydroxide (4.9 mL) at 0°C. Allow the mixture to warm to room temperature and stir overnight. Concentrate in vacuo and add ethyl acetate and saturated aqueous sodium chloride. Separate the layers. Extract the aqueous layer further with 9:1 dichloromethane:isopropyl alcohol.
Dry the combined organic layers from both reactions over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to ethyl acetate to 5% methanol in ethyl acetate to 10% methanol in ethyl acetate, to give the title compound (6.68 g, 35%). MS (ES) m/z = 336 [M]Preparation 36 N-Methyl-N-(methyleneamino)methan amine
,N=CH2 H3C-N
CH3
Combine dimethyl hydrazine (10.63 mL, 139.77 mmol) and paraformaldehyde (4.20 g, 0.33 eq). Stir the reaction for 1 hour. Add heptane (20 mL) and sodium sulfate (20 g). Stir 5 minutes, then filter off the sodium sulfate. Distill the filtrate with a short path distillation apparatus, collecting the title compound as a 75% w/w solution with heptane (10.3 g, 77%). 'H NMR (400 MHz, CDC13) 5 6.10 (m, 211), 2.80 (s, 611).

Preparation 37 tert-Butyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate
NU.NH

AddN-methyl-N-(methyleneamino)methanamine (1.30 g, 18.03 mmol) into chloroform (100 mL), then add 2,6-lutidine (3.2 mL, 1.5 eq). Cool the reaction mixture to 0°C and add trifluoroacetic anhydride (3.9 mL, 1.5 eq) over one minute. Allow the reaction to stir at 0°C for 10 minutes. Wash sequentially with 0.5 M aqueous HO, water, and 0.1 M aqueous sodium carbonate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to afford crude (E)-3-(dimethylhydrazono)-l,l.l-trifluoro-propan-2-one (1.80 g).
Add a portion of the intermediate (0.21 g, 1.25 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (0.33 g, 1.24 eq) in acetic acid (8 mL) and ammonium acetate (3.0 g). Heat at 80°C for 12 hours, then allow the mixture to cool to room temperature. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Stir for ten minutes, then extract twice with dichloromethane. Concentrate the organics in vacuo and purify by silica gel chromatography to give the title compound (0.19 g, 28%). 'H NMR (400 MHz, CD3OD) 8 7.40 (s, 1H), 4.15 (m, 2H), 2.90 (m, 3H), 1.90 (m, 211). 1.65 (m,2H), 1.40 (s,9H).
Preparation 37 (Alternate) tert-Butyl 4-(4-(trifluoromethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate

NyNH

H3C+CH3
CH3
Add sodium acetate (360.8 g, 2.0 eq) to water (3.54 L) at 30°C. Add 1,1-dibromo-3,3,3-trifluoroacetone (653.01 g, 1.10 mol) dropwise. Heat the mixture at 90°C under nitrogen for 1 hour. Add tert-butyl 4-formylpiperidine-l-carboxylate (470.00 g, 2.0 eq) to methanol (10 L) in another flask at 30°C. Add a solution of 28% aqueous ammonium hydroxide (2.53 L, 8.18 eq) into the methanol solution. Cool the first mixture to 30°C and add dropwise to the methanol solution over 45 minutes. Stir overnight under nitrogen. Remove solvent from the reaction mixture. Add water (2 L) and dichloromethane (6 L) and stir for 15 minutes at 25°C. Extract the aqueous layer with dichloromethane three times (1 L x3). Wash the organics with saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate and concentrate in vacuo. Add 5 L solution of 2% ethyl acetate in hexanes and stir at 30°C for 30 minutes. Filter the solid. wash with hexanes, and concentrate in vacuo to give the title compound as a white solid (618.0 g, 88%). 'H NMR (400 MHz, CDC13) 5 10.5 (s, 1H), 7.4 (s, 1H), 4.18 (s, 2 H), 2.98 (m, 1H), 2.80 (m, 2H), 2.01 (m, 2H), 1.71 (m, 2H), 1.45 (s, 9H).
Prepare the following compound essentially as described for tert-butyl 4-(4-
(trifluoromethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate:

Prep Compound Name MS (ES) m/z |M|4
38 tert-butyl 4-(4-tert'-butyl-lH-imidazol-2-yl)piperidine-l-
carboxylate 308
Preparation 39 tert-Butyl 4-(4-cyano-lH-imidazol-2-yl)piperidine-l-carboxylate

Combine tert-butyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)pipcridine-l-carboxylate (1.50 g, 4.70 mmol) and ammonium hydroxide (90 mL). Heat the reaction mixture at 60°C for two days. Let cool to room temperature, then filter via Buchner funnel. Wash the solids with water and hexanes to give the title compound as a white solid (1.08 g, 83%). MS (ES) m/z = 221 [M]+.
Preparation 40 tert-Butyl 4-( 1 H-imidazol-2-yl)piperidine-1 -carboxylate


HN./>N

Combine ammonium hydroxide (150 mL), re/t-butyl 4-formylpiperidinc-l-carboxylate (29.82 g, 139.81 mmol), and methanol (600 mL). Add ethanedial (16.10 ml 1.0 eq) (40 % in water) under nitrogen. Stir overnight. Then concentrate in vacuo to remove methanol. Dilute with water, then extract with dichloromethane. Wash the organics with saturated aqueous sodium chloride. Dry the organics over magnesium sulfate, filter, and concentrate in vacuo to give the title compound (33.30 g, 95%). MS (ES)m/z = 252[M]+.

Prepare the following compounds essentially as described for tert-butyl 4-(lII-imidazol-2-yl)piperidine-l-carboxylate:

Prep Compound Name MS (ES)
41 tert-butyl 4-(4-(3,3,3-trifluoropropyl)-lH-imidazol-2-yl)piperidine-1 -carboxylate 348
42 tert-butyl 4-(4-cyclobutyl-lH-imidazol-2-yl)piperidine-l-
carboxylate 306
43 tert-butyl 4-(4-methyl-1 H-imidazol-2-yl)piperidine-1 -carboxylate 266
44 tert-butyl 4-(4-propyl-lH-imidazol-2-yI)piperidine-l-carboxylate 294
45 terl-butyl 4-(4-(2-methoxyethyI)-1 H-imidazol-2-yl)piperidine-1 -
carboxylate 310
46 tert-butyl 4-(4-( 1 -methoxy-2-methyIpropan-2-yl)-1 H-imidazol-2-yl) piperidine-1-carboxylate 338
47 tert-butyl 4-(4-isobutyl-lH-imidazol-2-yl)piperidine-l-carboxylate 308

Preparations 48 and 49 tert-Butyl 4-(4,5-dichloro-lH-imidazol-2-yl)piperidine-l-carboxylate
and tert-Butyl 4-(4-chloro-lH-imidazol-2-yl)piperidine-l-carboxylate
HN. /M
HN. sM

CI ,CI CI
CH3 CH3
Add tert-bvXy\ 4-(lH-imidazol-2-yl)piperidine-l-carboxylate (6.00 g, 23.87 mmol) in dichloroethane (200 mL). Add N-chlorosuccinimide (3.19 g, 1.0 eq). Stir at room temperature under nitrogen for 14 hours. Concentrate the reaction mixture in vacuo. Purify by silica gel chromatography, eluting with hexanes to 9:1 hexanes:ethyl acetate to 4:1 hexanes:ethyl acetate to 2:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate, to give two major spots. Concentrate fractions containing the higher Rf spot in vacuo to give tert-butyl 4-(4,5-dichloro-lH-imidazol-2-yl)piperidine-l -carboxylate (2.25

g, 29%). MS (ES) m/z^ 321 [M]+. Concentrate fractions containing the lower spot in vacuo. Slurry the resulting solid into diethyl ether/chloroform, then filter. Concentrate the filtrate in vacuo to give tert-butyl 4-(4-chloro-lH-imidazol-2-yl)pipcridine-l-carboxylate (1.16 g, 17%). MS (ES) m/z = 286 [M]+.
Preparation 50 tert-Butyl 4-(4-isobutyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)pipcridinc-1 -
carboxylate

Combine tert-butyl 4-(4-isobutyl-lH-imidazol-2-yl)piperidine-l-carboxylate (1.50 g, 4.88 mmol) and potassium hydroxide (1.65 g, 6.0 eq) (freshly powdered) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 45°C under nitrogen. After 5 minutes, add l-(2-chloroethyl)pyrrolidine hydrochloride (1.08 g, 1.3 cq). Stop heating after 2 hours. Add water and extract with ethyl acetate. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound as a yellow oil (2.11 g, 100%). MS (ES) m/z = 405 [M]+.
Prepare the following compounds essentially as described for tert-butyl4-(4-isobutyl-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine-l -carboxylate (Note 1: A mix of 4- and 5-substituted alkylation isomers may be obtained. In some cases, purification by normal phase chromatography can afford the desired isomer. Note 2: Use of the reagents 2-(2-bromoethoxy)tetrahydro-2H-pyran or 2-(2-chloroethoxy)tetrahydro-2H-pyran can afford the 2-(tetrahydro-2H-pyran-2-yloxy)ethyl compounds):

Prep

Compound Name

MS (ES) m/z\M\*

51 tert-butyl 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(3,3,3-tnfluoropropyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 445
52 tert-butyl 4-(4-( 1 -methylcyclobutyl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)pipcridinc-1 -carboxylate 417
53 tert-butyl 4-(4-cyclobutyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1H-imidazol-2-yl)piperidine-l-carboxylate 403
54 tert-butyl 4-(l-(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-l-carboxylate 349
55 tert-butyl 4-(4-(l-methylcyclopropyl)-l-(2-(pyrrolidin-l-yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 403
56 tert-butyl 4-(4-cyclopentyl-l-(2-(pyrrolidin-1 -yl)ethyl)-1H-imidazol-2-yl)piperidine-l-carboxylate 417
57 tert-butyl 4-(4-cyclohexyl-1 -(2-(pyrrolidin-l-yl)ethyl)-1H-imidazol-2-yl)piperidine-1 -carboxylate 431
58 tert-butyl 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(2,2,2-trifluorocthyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 431
59 tert-butyl 4-(4-cyano-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 374
60 tert-butyl 4-(4-tert-butyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1H-imidazol-2-yl)piperidine-l-carboxylate 405
61 tert-butyl 4-(4,5-dichloro-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate 417
62 tert-butyl 4-(4-ethyl-1 -(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 408
63 tert-butyl 4-(4-propyl-l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 422 477
64 tert-butyl 4-( 1 -(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1II-imidazol-2-yl)piperidine-1 -carboxylate

65 tert-butyl 4-(l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-yl)piperidine-1 -
carboxylate 464
66 tert-butyl 4-(l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(trifluoromethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 448
67 tert-butyl 4-(4-methyl-1 -(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1 H-imidazoI-2-yl)piperidine-1 -carboxylate 394
68 tert-butyl 4-(4-isopropyl-1 -(2-(tetrahydro-2H-pyran-2-yloxy) ethyl)-lH-imidazol-2-yl) piperidine-1-carboxylate 422
69 tert-butyl 4-(4-(2-methoxyethyl)-1 -(2-(tetrahydro-2H-pyran-2-yloxy) ethyl)-lH-imidazol-2-yl) piperidine-1-carboxylate 438
70 tert-butyl 4-(4-cyclopentyI-l-(2-(tetrahydro-2H-pyran-2-yloxy) ethyl)-1 H-imidazol-2-yl) piperidine-1 -carboxylate 448
71 tert-butyl 4-(l-(2-(tetrahydro-2H-pyran-2-yloxy) ethyl)-4-(2,2,2-trifluoroethyl)-1 H-imidazol-2-yl) piperidine-1 -carboxylate 462
72 tert-butyl 4-(4-( 1 -methoxy-2-methyIpropan-2-yl)-1 -(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-lH-imidazol-2-yl)pipcridine-
1-carboxylate 466
73 tert-butyl 4-(4-chloro-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2- 383

yl)piperidine-l -carboxylate
74 tert-butyl 4-(4-butyl-1 -(2-(pyrrolidin-1 -yljethyl)-1 H-imidazol-2-yl)piperidine-l -carboxylate 405
75 tert-butyl 4-(4-butyl-l-(2-(tetrahydro-2H-pyran-2-yloxy) ethyl)-1 H-imidazol-2-yl) piperidine-1 -carboxylate 436
76 tert-butyl4-(4-(4-methyltetrahydro-2H-pyran-4-yl)-l-(2-
(tetrahydro-2H-pyran-2-yloxy) ethyl)-lH-imidazol-2-yl)
piperidine-1 -carboxylate 478
77 tert-butyl4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(trirluoromethyl)-lH-imidazol-2-yl)piperidine-1 -carboxylate 417
Preparation 78 tert-B\ity\ 4-( 1 -(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tetrahydro-2H-pyran-4-y 1)-
imidazol-2-yl)piperidine-1 -carboxylate O-

Combine tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-yl)pipcridinc-1-carboxylate (5.84 g, 17.40 mmol) and potassium hydroxide (5.91 g, 6.0 cq) (freshly powdered) in dimethyl sulfoxide (30 mL). Heat the reaction mixture to 45°C under nitrogen. After 15 minutes, add 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.90 mL, 1.1 eq). Continue to heat the reaction overnight. Add water and extract with ethyl acetate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate, to give the title compound as a thick yellow oil (6.94 g, 86%). MS (ES) m/z = 464 [M]+.
Preparation 79

tert-Butyl 4-(4-(trifluoromethyl)-l-(2-pyrrolidin-l-ylethyl)-lH-imidazol-2-yI)pipcridinc-
1-carboxylate succinate
NV% HO
N OK
oAo 0H
H3C+CH3
CH3
Add l-(2-chloro-ethyl)-pyrrolidinium chloride (73.50 g, 1.15 eq) to a mixture of tert-butyl 4-(4-(trifluoromethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate (120.00 g, 375.79 mmol) and potassium hydroxide (54.82 g, 2.60 eq) in dimethyl sulfoxide (1.1 L). Stir the resulting suspension at 50°C overnight. Cool the reaction mixture to room temperature and add ice/water (1.50 1). Extract with ethyl acetate (3x 500 ml). Wash the organics with water (2x 300 mL) and saturated aqueous sodium chloride (300 mL), dry over anhydrous sodium sulfate. Purify by silica gel chromatography, eluting with 5% to 15% isopropyl alcohol in dichloromethane, to give a mixture of tert-butyl 4-(4-(trifluoromethyl)-l-(2-pyrrolidin-l-ylethyl)-lH-imidazol-2-yl)piperidinc-l-carboxylatc (122.00 g, 78%) and tert-butyl 4-(5-(trifluoromethyl)-l-(2-pyrrolidin-l-ylethyl)-l II-imidazol-2-yl)piperidine-l-carboxylate (14.00 g, 9%). Add isopropyl alcohol (470 mL) and heat to 70°C. Add a solution of butanedioic acid (35 g, 1 eq) in isopropyl alcohol (350 mL) preheated at 75°C. Stop heating and let stir at room temperature overnight. Filter the solid and wash with isopropyl alcohol (300 mL). Suspend the solid in isopropyl alcohol (500 mL) and stir 15 minutes. Filter and stir the solid in isopropyl alcohol (500 mL) 15 minutes one more time, then filter to give the title compound (124.00 g. 82%) as a white solid. MS (ES) m/z = 417 [M]+.
Preparation 80 tert-Butyl 4-(4,5-dibromo-l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-lH-imidazol-2-
yl)piperidine-1 -carboxylate

Add tert-butyl 4-(l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate (121.70 g, 320.69 mmol) in dichloromethane (1750 mL). Add N-bromosuccinimide (114.15 g, 2.0 eq). Stir at room temperature under nitrogen. Stop the reaction after 90 minutes. Dilute the reaction mixture with water and extract with dichloromethane. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 1:1 hexanes:ethyl acetate to ethyl acetate, to give the title compound as a light-orange sticky oil (125.40 g, 73%). MS (ES) m/z = 538 [M]Preparation 81 tert-Butyl 4-(4-bromo-l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-lH-imidazol-2-
yl)piperidine-1 -carboxylate Br

Add tert-bvXy\ 4-(4,5-dibromo-l-(2-(tetrahydro-2H-pyran-2-yloxy)cthyl)-llI-imidazol-2-yl)piperidine-l-carboxylate (46.00 g 85.61 mmol) in tetrahydrofuran (1 L). Cool to -78°C under nitrogen. Add 1.6 M butyllithium in hexanes (90.97 mL, 1.7 eq) dropwise over 15 minutes. Maintain the internal temperature below -65°C. After 65 minutes, add isopropyl alcohol (50 mL). Allow to warm to room temperature over 2hr

Dilute with saturated aqueous ammonium chloride, then extract with ethyl acetate three times. Wash the organics with saturated aqueous sodium chloride. Dry over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound (43.00 g. 100%). MS (ES) m/z = 460 [M]+.
Preparation 82 tert-Butyl4-(4-cyclopropyl-1 -(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1 H-imidazol-2-
yl)piperidine-1 -carboxylate



O. .0

Add tert-butyl 4-(4-bromo-l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-l II-imidazol-2-yl)piperidine-l-carboxylate (1.82 g, 3.97 mmol), cyclopropylboronic acid (0.44 g, 1.3 eq), tricyclohexylphosphine (0.11 g, 0.1 eq), and potassium phosphate (2.95 g, 3.5 eq) in toluene (18 mL) and water (0.9 mL). Degas with nitrogen for 5 minutes. Add palladium acetate (0.045 g, 0.05 eq) and heat at 90°C overnight. Stop heating after 12 hrs. Dilute with water then extract with ethyl acetate three times. Dry over anhydrous magnesium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 0-20-50% ethyl acetate/hexanes, then with 1-3-5-7%) methanol/dichloromethane, to give the title compound (0.61 g, 37%). MS (ES) m/z ^ 420 [M]+.
Preparation 83 2-(4-Ethyl-2-(piperidin-4-yl)-1 H-imidazol-1 -yl)ethanol dihydrochloride


HCI HCI

Combine tert-butyl 4-(4-ethyl-1 -(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-11I-imidazol-2-yl)piperidine-l-carboxylate (4.70 g, 11.53 mmol), dichloromethane (100 mL). and methanol (50 mL). Add hydrogen chloride (20 mL) (4 M in dioxane) slowly. Stir overnight under nitrogen. Concentrate in vacuo to give the title compound (3.40 g, 100%). MS (ES) m/z = 224 [M]+.
Prepare the following compounds essentially as described for 2-(4-ethyl-2-(piperidin-4-yl)-lH-imidazol-l-yl)ethanol dihydrochloride:

Prep Compound Name MS (ES) ifi/z[M]J
84 2-(4-methyl-2-(piperidin-4-yl)-lH-imidazol-l-yl)ethanol dihydrochloride 210
85 2-(2-(piperidin-4-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)ethanol
dihydrochloride 264
86 2-(4-butyl-2-(piperidin-4-yl)-1 H-imidazol-1 -yl)ethanol dihydrochloride 252
87 2-(2-(piperidin-4-yl)-4-propyl-1 H-imidazol-1 -yl)ethanol dihydrochloride 238
88 2-(2-(piperidin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-1 -yl)ethanol dihydrochloride 280
89 2-(4-cyclopropyl-2-(piperidin-4-yl)-1 H-imidazol-1 -yl)ethanol
dihydrochloride 236
90 2-(4-(4-methyltetrahydro-2H-pyran-4-yl)-2-(piperidin-4-yl)-lH-imidazol-1 -yl)ethanol dihydrochloride 294
90a 2-(2-(Piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1 H-imidazol-1 -yl)ethanol dihydrochloride 278
Preparation 91 tert-Buty] 4-(4-bromo-1 -(2-hydroxyethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylatc

Combine tert-butyl 4-(4-bromo-l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-l 11-imidazol-2-yl)piperidine-l-carboxylate (5.00 g, 10.91 mmol), tetrahydrofuran (150 ml). and 1 M aqueous hydrochloric acid (50 mL); let stir overnight at room temperature. Dilute with ethyl acetate. Wash with excess 1M aqueous sodium hydroxide, followed by saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate. filter, and concentrate in vacuo to give the title compound as a yellow foam (3.84 g, 94%). MS (ES) m/z = 376 [M]+.
Prepare the following compounds essentially as described for tert-Butyl 4-(4-bromo-1 -(2-hydroxyethyI)-l H-imidazol-2-yl)piperidine-1 -carboxylate:

Prep
92
93
94
95

Compound Name
tert-butyl 4-( 1 -(2-hydroxyethyl)-4-propyl-1H-imidazol-2-yl)piperidine-1 -carboxylate
tert-butyl4-(l-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-yl)piperidine-1 -
carboxylate
tert-butyl 4-( 1 -(2-hydroxyethyl)-4-(trifluoromethy 1)-1 H-imidazol-2-yl)piperidine-1 -carboxylate
^r/-butyl4-(l-(2-hydroxyethyl)-4-methyl-lH-imidazol-2-yl) piperidine-1 -carboxylate

MS (ES) m/z [M]+ or
■H NMR
338
380
364
iINMR(DMSO,
400MHz) 8 6.70 (s, 1H), 4.91 (m, 1H). 3.97 (m, 311), 3.91 (m,2H),
2.90 (m, 311), 2.00 (s, 3H), 1.70 (m,2H), 1.60
(m,4H), 1.40 (s, 911)

96
97
98

tert-butyl 4-(4-isopropyl-1 -(2-hydroxyethyl)-1H-imidazol-2-yl) piperidine-1 -carboxylate
tert-butyl 4-(l-(2-hydroxyethyl)-4-(2-methoxyethyl)-1 H-imidazol-2-yl) piperidine-1 -carboxylate
tert-butyl 4-(4-cyclopentyl-1 -(2-hydroxyethyl)-1H-

338
354
364

imidazol-2-yl) piperidine-1-carboxylate
99 tert-butyl 4-( 1 -(2-hydroxyethyl)-4-(2,2,2-
trifluoroethyl)-lH-imidazol-2-yl) piperidine-1 -
carboxylate 378
100 te/7-butyl 4-(4-cyclopropyl-1 -(2-hydroxyethyl)-1H-imidazol-2-yl)piperidine-l-carboxylate 336
101 tert-butyl 4-( 1 -(2-hydroxyethyl)-4-( 1 -methoxy-2-
methylpropan-2-yl)-1 H-imidazol-2-yI)piperidine-1 -
carboxylate 383
Preparation 102 tert-Butyl 4-(l-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-
yl)piperidine-1 -carboxylate O'

Combine tert-butyl 4-(l-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-yl)piperidine-l-carboxylate (6.88 g, 14.84 mmol), tetrahydrofuran (136 mL) and 1 N aqueous hydrochloric acid (25 mL). Stir the reaction at room temperature overnight. Dilute with ethyl acetate and wash with saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate. Extract the combined aqueous layers with 9:1 dichloromethane:isopropyl alcohol. Dry the combined organic layers over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 50% ethyl acetate in hexanes to ethyl acetate to 10% methanol in ethyl acetate to 10% methanol in dichloromethanc, to give the title compound as a white solid (4.48 g, 79%). MS (ES) m/z - 380 |_M]+.
Preparation 103 tert-Butyl 4-(4-vinyl-1 -(2-hydroxyethyI)-1 H-imidazol-2-yl)piperidine-1 -carboxylate

Add tert-butyl 4-(4-bromo-1 -(2-hydroxyethyl)-1 H-imidazol-2-yl)pipcridinc-1 -carboxylate (42.00 g, 112.22 mmol) in 1,4-dioxane (400 ml) and water (200 mL). Add potassium phosphate, tribasic, N-hydrate (47.64 g, 2.0 eq) and dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane (5.76 g, 0.12 eq). Degas with nitrogen for 5 minutes. Add 4,4,5,5-tetramethyl-2-vinyl-l,3,2-dioxaborolane (30.25 mL, 1.5 eq) then degas for another 10 minutes. Add palladium acetate (1.26 g, 0.05 eq) and reflux at 120°C overnight. Stop heating after 12 hrs. Filter through Celite ®. Wash with dichloromethane and methanol. Concentrate to dryness in vacuo. Dilute with saturated aqueous sodium chloride then extract with ethyl acetate three times. Dry over anhydrous sodium sulfate and concentrate in vacuo. Purify by silica gel chromatography, eluting with 50-90% ethyl acetate/hexanes, to give the title compound as a yellow foam (20.50 g. 56%). MS (ES) m/z = 322 [M]+.
Preparation 104 tert-Butyl 4-(4-ethyl-1 -(2-hydroxyethyl)-1 H-imidazol-2-yl)piperidinc-1 -carboxylate
CH,


Add 10% palladium on carbon (2.10 g) in ethanol (50 mL). Then add a solution of tert~butyl 4-( 1 -(2-hydroxyethyl)-4-vinyl-1 H-imidazol-2-yl)piperidine-1 -carboxylatc (20.00 g, 62.22 mmol) in ethanol (200 mL). Cycle through nitrogen and vacuum three times, then hydrogen and vacuum three times. Allow to stir at room temperature under 1 atmosphere hydrogen. After two hours, filter through Celite ®. Wash with methanol. Concentrate the filtrate in vacuo to give a light yellow solid as the title compound (20.00 g, 99%). MS (ES) m/z = 324 [M]+.
Preparation 105
5-(4-(4-Ethyl-1 -(2-hydroxyethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-3 -(2,2.2-
trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(HI)-one
CK

Add 5-chloro-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-dJpyrimidin-2(lH)-one (0.28 g, 1.05 mmol), 2-(4-ethyl-2-(piperidin-4-yl)-lH-imidazol-l-yl)cthanol dihydrochloride (0.38 g, 1.3 eq), methanol (15 mL) and diisopropylethylamine (0.91 mL. 5.0 eq) into a 20 mL microwave vial. Seal the tube and heat in a microwave reactor to 150°C, for 1 hour. Filter through silica gel, eluting with 10% ammonia-methanol/dichloromethane. Concentrate the filtrate in vacuo. Purify by silica gel chromatography, eluting with 3:1 ethyl acetate/ methanol, to give the title compound as a yellow foam (0.67 g, 70%). MS (ES) m/z = 454 [M]+.
Prepare the following compounds essentially as described for 5-(4-(4-ethyl-l-(2-hydroxyethyl)-lH-imidazol-2-yl)piperidin-l-yl)-3-(2,2,2-tritluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(lH)-one:

Prep Compound Name MS (ES) m/z [M]1
106 (R)-4-(4-(4-ethyl-1 -(2-hydroxyethyl)-1 H-imidazol-2-yl)piperidin-l-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8II)-one 385
107 (R)-4-(4-( 1 -(2-hy droxyethyl>4-methyl-1 H-imidazol-2-yl)piperidin-l-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one 371
108 (R)-4-(4-( 1 -(2-hydroxyethyl)-4-(trifluoromethyl)-1 H-imidazol-2-yl)piperidin-l-yl)-5-methyl-5,6-dihydropyridof2,3-d]pyrimidin-
7(8H)-one 425
109 (R)-4-(4-(4-butyl-l-(2-hydroxyethyl)-1 H-imidazol-2-yl)piperidin-l-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one 467
110 (R)-4-(4-(4-butyl-l-(2-hydroxyethyl)-lH-imidazol-2-yl)piperidin-l-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one 413
111 (R)-4-(4-(l-(2-hydroxyethyl)-4-propyl-lH-imidazol-2-
yl)piperidin-l-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one 453
112 (R)-4-(4-(4-ethyl-l -(2-hydroxyethyl)-1 H-imidazol-2-yl)pipcridin-l-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one 439
113 (R)-4-(4-(l-(2-hydroxyethyl)- 4-(tetrahydro-2H-pyran-4-yl)-1H-
imidazol-2-yl)piperidin-l-yl)-5-methyl-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one 441
114 (R)-4-(4-(4-cyclopropyl-1 -(2-hydroxyethyl)-1 H-imidazol-2-
yl)piperidin-l-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one 451
115 (R)-4-(4-( 1 -(2-hydroxyethyl)- 4-(4-methyltetrahydro-2H-pyran-4-
yl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-(trifluoromethyl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-one 509
115a (R)-4-(4-(l-(2-Hydroxyethyl)-4-propyl-lM-imidazol-2-yl)piperidin-l-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one 399
115b (R)-4-(4-( 1 -(2-Hy droxyethyl)-4-(2,2,2-trifluoroethyl)-1H-
imidazol-2-yl)piperidin-l-yl)-5-methyl-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one 439
115c (R)-4-(4-(l-(2-Hydroxyethyl)-4-(4-methyltetrahydro-2H-pyran-4-
yl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-methyl-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-one 455
Preparation 116 tert-Butyl 4-(4-bromo-l-(2-(methylsulfonyloxy)ethyl)-lH-imidazol-2-yl)pipcridinc-l-
carboxylate


Combine tert-butyl 4-(4-bromo-l-(2-hydroxyethyl)-lII-imidazol-2-yl)piperidine-1-carboxylate (3.84 g, 10.26 mmol), dichloromethane (60 mL), and tricthylaminc (4.29 mL, 3.0 eq). Place under nitrogen and cool to 0°C. Add methanesulfonyl chloride (0.95 mL, 1.2 eq) dropwise. After 15 minutes, quench with saturated aqueous sodium bicarbonate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound (4.45 g, 96%). MS (ES) m/z - 452 [M]+.
Prepare the following compounds essentially as described for tert-butyl 4-(4-bromo-1 -(2-(methylsulfonyloxy)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylatc:

Prep Compound Name MS (ES) m/zlM]1
117 tert-butyl 4-(4-ethyl-l-(2-(methylsulfonyloxy)ethyl)-lH-imidazol-2-yl)piperidine-1 -carboxylate 402
118 ten-butyl 4-(l -(2-(methylsulfonyloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 458
119 tert-butyl 4-( 1 -(2-(methylsulfonyloxy)ethyl)-4-propyl-1H-imidazol-2-yl)piperidine-1 -carboxylate 416
120 (R)-2-(4-ethyl-2-(l-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-
d]pyrimidin-4-yl)piperidin-4-yl)-1 H-imidazol-1 -yl)ethyl
methanesulfonate 463
121 2-(4-ethyl-2-(l-(7-oxo-6-(2,2,2-trifluoroethyl)-5,6,7,8-
tetrahydropyrimido[4,5-d]pyrimidin-4-yl)piperidin-4-yl)-11I-
imidazol-l-yl)ethyl methanesulfonate 532
122 (R)-2-(4-methyl-2-(l-(5-methyl-7-oxo-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-lH-
imidazol-1 -yl)ethyl methanesulfonate 449
123 (R)-2-(2-(l-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-
d]pyrimidin-4-yl)piperidin-4-yl)-4-(trifluoromethyl)-lH-imidazol-
l-yl)ethyl methanesulfonate 503
124 tert-butyl 4-(4-methyl-l-(2-(methylsulfonyloxy) ethyl)-1H- 388

imidazol-2-yl) piperidine-1 -carboxylate
125 tert-butyl 4-(4-isopropyl-l-(2-(methylsulfonyloxy) ethyl)- 1H-imidazol-2-yl) piperidine-1 -carboxylate 416
126 tert-butyl 4-(4-(2-mcthoxycthyl)-1 -(2-(mcthylsulfonyloxy) cthyl)-lH-imidazol-2-yl) piperidine-1-carboxylate 433
127 fer/-butyl 4-(4-cyclopentyl-1 -(2-(methylsulfonyloxy) ethyl)-1H-imidazol-2-yl) piperidine-1-carboxylate 442
128 tert-butyl 4-(l-(2-(methylsulfonyloxy) ethyl)-4-(2,2,2-trifluoroethyl)-1 H-imidazol-2-yl) piperidine-1 -carboxylate 456
129 /erf-butyl 4-(4-cyclopropyl-l-(2-(methylsulfonyloxy)ethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate 414
130 tert-butyl 4-(4-( 1 -methoxy-2-methylpropan-2-yl)-1 -(2-(methyl sulfonyloxy)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 443
131 tert-butyl 4-(l-(2-(methylsulfonyloxy)ethyl)-4-(trifIuoromethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 442
132 (R)-2-(2-(l-(7-oxo-5-trifluoromethyl-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-butyl-lIT-
imidazol-1 -yl)ethyl methanesulfonate 545
133 (R)-2-(2-(l-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-butyl-1 H-imidazol-1 -yl)ethyl
methanesulfonate 491
134 (R)-2-(2-(l-(7-oxo-5-trifluoromethyl-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-propyl-
1 H-imidazol-1 -yl)ethyl methanesulfonate 531
135 (R)-2-(2-(l-(7-oxo-5-trifluoromethyl-5,6,7,8-
tetrahydropyrido[2,3-dlpyrimidin-4-yl)piperidin-4-yl)-4-ethyl-111-
imidazol-1 -yl)ethyl methanesulfonate 517
136 (R)-2-(2-(l-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-
d]pyrimidin-4-yl)piperidin-4-yl)-4-(tetrahydro-2H-pyran-4-yl)-
1 H-imidazol-1 -yl)ethyl methanesulfonate 519
137 (R)-2-(2-(l-(7-oxo-5-trifluoromethyl-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-
cyclopropyl-1 H-imidazol-1 -yl)ethyl methanesulfonate 529
138 (R)-2-(2-(l-(7-oxo-5-trifIuoromethyl-5,6,7,8-
tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)- 4-(4-
methyltetrahydro-2H-pyran-4-yl)-1 H-imidazol-1 -yl)ethyl
methanesulfonate 587
138a (R)-2-(2-(l-(5-Methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-propyl-1 H-imidazol-1 -yl)ethyl
methanesulfonate 477
138b (R)-2-(2-(l-(5-Methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-
d]pyrimidin-4-yl)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1H-
imidazol-1 -yl)ethyl methanesulfonate 517
138c (R)-2-(2-(l-(5-Methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-
d]pyrimidin-4-yl)piperidin-4-yl)-4-(4-methyltetrahydro-2H-pyran-
4-yl)-1 H-imidazol-1 -yl)ethyl methanesulfonate 533

Preparation 139 re^Butyl4-(l-(2-(methylsulfonyloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-
2-yl)piperidine-1 -carboxylate O-

Combine tert-butyl 4-(l-(2-hydroxyethyl)-4-(tetrahydro-2H-pyran-4-yl)-l H-imidazol-2-yl)piperidine-l-carboxylate (4.40 g, 11.60 mmol) and triethylamine (4.9 ml. 3.0 eq) in dichloromethane (72 mL). Cool to 0°C and add methanesulfonyl chloride (1.1 mL, 1.2 eq). After 1 hour, dilute with additional dichloromethane and saturated aqueous sodium bicarbonate. Separate the layers. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give the title compound as a light yellow solid (5.05 g, 95%). MS (ES) m/z = 458 [M]+.
Preparation 140 terM3utyl 4-(4-bromo-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -
carboxylate Br,

Combine tert-butyl 4-(4-bromo-1 -(2-(methylsulfonyloxy)ethyl)-1 H-imidazol-2-yl)piperidine-l-carboxylate (4.45 g, 9.84 mmol), dimethylformamide (25 mL), and

pyrrolidine (2.46 mL, 3.0 eq) under nitrogen. Heat the reaction mixture at 50°C overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash with water followed by saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give the title compound (4.12 g, 98 %). MS (ES) m/z = 427 [M]+.
Prepare the following compounds essentially as described for tert-butyl 4-(4-
bromo-1 -(2-(pyrrolidin-1 -yl)ethyl)-l H-imidazol-2-yl)piperidine-1 -carboxylate:

Prep Compound Name MS (ES) m/z\M\'
141 tert-butyl 4-(4-propyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 391
142 tert-butyl 4-(4-methyl-l-(2-(pyrrolidin-l-yI)ethyI)-lH-imidazol-2-yl)piperidine-1 -carboxylate 363
143 (S)-tert-butyl 4-( 1 -(2-(3-hydroxypyrrolidin-1 -y I)ethyI)-4-isopropyl-1 H-imidazol-2-yl)piperidine-1 -carboxylate 407
144 (R)-terZ-butyl 4-(l-(2-(3-hydroxypyrrolidin-l-yl)ethyl)-4-isopropyl-1 H-imidazoI-2-yl)piperidine-1 -carboxylate 407
145 tert-butyl 4-( 1 -(2-(dimethylamino)ethyl)-4-ethyl-1 H-imidazol-2-yl)piperidine-1 -carboxylate 351
146 tert-butyl4-[l-[2-(cyclopentylamino)ethyl]-4-ethyl-imidazol-2-y 1] piperidine-1 -carboxylate 391
147 tert-butyl 4-( 1 -(2-(^r/-butylamino)ethyl)-4-cyclopentyI-111-imidazol-2-yl)piperidine-1 -carboxylate 419
148 tert-butyl4-( 1 -(2-(^rr-butyIamino)ethyl)-4-(trifluoromethyl)-1 H-imidazoI-2-yI)piperidine-1 -carboxylate 419
149 tert-butyl 4-( 1 -(2-(tert-butylamino)ethyI)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 435
150 ^r/-butyl 4-( 1 -(2-(tert-butylamino)ethyl)-4-(2,2,2-trifluoroethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 433
151 tert-butyl4-( 1 -(2-(cycIopropylmethylamino)ethyl)-4-ethyl-1II-imidazol-2-yl)piperidine-1 -carboxylate 377
152 tert-butyl 4-( 1 -(2-(te^butylamino)ethyl)-4-isopropyl-1H-imidazol-2-yl)piperidine-1 -carboxylate 393
153 tert-butyl4-(4-ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 377
154 tert-butyl 4-(4-ethyl-1 -(2-(isopropylamino)ethyl)-111-imidazol-2-yl)piperidine-1 -carboxylate 365
155 tert-butyl4-(4-isopropyl-1 -(2-(isopropylamino)ethyl)-1H-imidazol-2-yl)piperidine-1 -carboxylate 379
156 tert-butyl 4-[4-cyclopropyI-1 -(2-pyrrolidin-1 -ylethyl)imidazol-2-yl]piperidine-l-carboxylate 389
157 tert-butyl 4-[4-isopropyl-l-(2-pyrrolidin-l-ylethyl)imidazoI-2- 391

yl] piperidine-1 -carboxylate
158 tert-butyl 4-( 1 -(2-(cyclobutylamino)ethyl)-4-(trifluoromethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate 417
159 tert-butyl 4-( 1 -(2-(tert-butylamino)ethyl)-4-cycIopropyl-1H-imidazol-2-yl)piperidine-1 -carboxylate 392
160 tert-butyl 4-( 1 -(2-(tert-butylamino)ethyl)-4-ethyl-1 H-imidazoI-2-yl)piperidine-l-carboxylate 377
161 tert-butyl 4-(4-(2-methoxyethyl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-1H-imidazol-2-yl)piperidine-l-carboxylate 407
162 tert-butyl 4-(4-( 1 -methoxy-2-methylpropan-2-yl)-1 -(2-
(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -
carboxylate 435
163 tert-butyl 4-(4-ethyl-l-(2-(tetrahydropyran-4-ylamino)ethyl)-lM-imidazol-2-yl)piperidine-l-carboxylate 407
Preparation 164 tert-Butyl 4-( 1 -(2-(pyrrolidin-1 -yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-
yl)piperidine-1 -carboxylate O

Combine tert-butyl 4-( 1 -(2-(methylsulfonyloxy)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-yl)piperidine-l-carboxylate (2.02 g, 4.42 mmol), pyrrolidine (1.1 ml., 3.0 eq), and dimethylformamide (19 mL). Heat the reaction mixture to 50°C overnight. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate the layers. Wash the organics with water. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, cluting with hexanes to ethyl acetate to 10% methanol in dichloromethane, to give the title compound as a yellow oil (1.79 g, 93%). MS (ES) m/z - 433 [M]+.
Preparation 165

tert-Butyl 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-vinyl-lH-imidazol-2-yl)piperidine-
carboxylate CH,

Add tert-butyl 4-(4-bromo-l-(2-(pyrrolidin-l-yl)ethyl)-lII-imidazol-2-yl)piperidine-l-carboxylate (0.26 g, 0.60 mmol) in 1,4-dioxane (4 mL) and water (1 mL). Add potassium phosphate, tribasic, N-hydrate (0.26 g, 2.0 eq) and dicyclohexyl-|2-(2,6-dimethoxyphenyl)phenyl]phosphane (0.036 g, 0.15 eq). Add 4,4,5,5-tetramcthyl-2-vinyl-l,3,2-dioxaborolane (0.22 mL, 2.05 eq) and degas for 10 minutes. Add bis(dibenzylideneacetone)palladium(0) (0.03 g, 0.06 eq) and reflux at 150°C for l hour. Filter through Celite ®. Wash with dichloromethane. Concentrate the filtrate to dryness in vacuo. Purify by silica gel chromatography, eluting with 25% methanol/ethyl acetate. to give the title compound as a yellow foam (0.14 g, 38%). MS (ES) m/z = 375 \M]
Preparation 166 4-(4-Bromo-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine trihydrochloridc
Br.
HCIHCI HCI
Combine / i
180 N-(2-(4-isopropyl-2-(piperidin-4-yl)-1 H-imidazol-1 -yl)ethyl)-2-methylpropan-2-amine 293
317
181 4-(4-cyclopentyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine hydrochloride

182 4-(4-cyclohexyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-
yl)piperidine 330
183 N-(2-(4-isopropyl-2-(piperidin-4-yl)-1 H-imidazol-1 -yl)ethyl)propan-2-amine trihydrochloride 279
184 4-(4-cyclopropyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-
yl)piperidine 289
185 4-(4-isopropyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-
yl)piperidine 291
186 N-(2-(2-(piperidin-4-yl)-4-(trifluoromethyl)-1 H-imidazol-1 - 317

yl)ethyl)cyclobutanamine
187 4-(4-vinyl-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine tris(2,2,2-trifluoroacetate) 275 274
188 2-(piperidin-4-yl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazole-4-carbonitrile trihydrochloride

189 4-(4-isobutyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine trihydrochloride 305
190 4-(4-(2,2,2-trifluoroethyl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine trihydrochloride
191 4-(4-ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine
trihydrochloride 277 305
192 4-(4-tert-butyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine trihydrochloride

193 N-(2-(4-cyclopropyl-2-(piperidin-4-yl)-1 H-imidazol-1 -yl)ethyl)-2-methylpropan-2-amine 291
194 N-(2-(4-ethyl-2-(piperidin-4-yl)-lH-imidazol-l-yl)ethyl)-2-methylpropan-2-amine trihydrochloride 279
195 4-(4-( 1 -methoxy-2-methylpropan-2-yl)-1 -(2-(pyrrolidin-1 -yl) ethyl)-1 H-imidazol-2-yl) piperidine 335
196 4-(4,5-dichloro-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)
piperidine 317
197 4-(4-chloro-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl) piperidine trihydrochloride 283
198 4-(4-butyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl) piperidine
trihydrochloride 305
199 N-(2-(4-ethyl-2-(piperidin-4-yl)-1 H-imidazol-1 -yl)ethyl)tetrahydropyran-4-amine trihydrochloride 307
200 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)piperidine trihydrochloride 317
Preparation 201 4-(4-(Tetrahydro-2H-pyran-4-yl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-
yl)piperidine
0-\J HCI
^\ HCI
r^\ HCI
H Combine tert-butyl 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(tetrahydro-2II-pyran-4-yl)-lH-imidazol-2-yl)piperidine-l-carboxylate (1.74 g, 4.03 mmol), dichloromethane (53

mL) and methanol (21 mL). Add 4 M hydrogen chloride in 1,4-dioxane (10.4 mL. 10.3 eq). After one hour, concentrate in vacuo. Dry the resulting residue under vacuum to give the title compound as a white solid (1.67 g, 94%). MS (ES) m/z = 333 [M|Preparation 202 4-(4-Trifluoromethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)pipcridine

H Add tert-butyl4-(4-(trifluoromethyl)-1 -(2-pyrrolidin-1 -ylethyl)-1 H-imidazol-2-yl)piperidine-l-carboxylate succinate (120 g, 224.48 mmol) in methanol (720 mL) to 37% aqueous hydrogen chloride (76.08 mL, 4 eq) at room temperature. Stir the solution at 50°C. Concentrate the reaction mixture. Add 500 mL water and wash with methyl tert-b\x\y\ ether (200 mL). Basify the aqueous solution with 6M aqueous sodium hydroxide at 0 °C. Extract with ethyl acetate (4x200 mL). Dry the organics over anhydrous sodium sulfate and concentrate in vacuo to give the title compound (68 g. 96%). MS (ES) m/z = 317 [M]+.

Example 1 (R)-4-(4-( 1 -(2-(tert-Butylamino)ethyl)-4-(trifluoromethyl)-1 H-imidazol-2-yl)pipcridin-yl)-5-methyI-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one


HX XhL
3X
CH,

Add (R)-2-(2-(l-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-dlpyrimidin-4-yl)piperidin-4-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)ethyl methanesulfonate (0.50 g, 0.99 mmol), tert-butylamine (0.52 mL, 7.1 eq), and triethylamine (0.69 ml, 5.0 cq) in dimethylformamide (5 mL). Heat to 50°C in a sealed tube for 48 hours. Dilute the solution with saturated aqueous sodium chloride. Add the mixture into ethyl acetate. Wash the organics with saturated aqueous sodium chloride and concentrate in vacuo. Purify by silica gel chromatography, eluting with 20% ethanol/acetone, to give the title compound (0.27 g, 55%). MS (ES) m/z = 480 [M]+.
Prepare the following compounds essentially as described for (R)-4-(4-(l-(2-(tert-butylamino)cthyI)-4-(trifluoromethyl)-lH-imidazol-2-yl)piperidin-l-yl)-5-mcthyl-5.6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (alternative purification for Ex 3; concentrate the reaction mixture and filter from isopropanol to give the desired product as the mesylate salt):

MS
Ex Compound Name Structure (ES) m/z JM]+

CH,
M M
(R)-4-(4-( 1 -(2-(azetidin-1 -yl)ethyl)-4-
? ethyl-lH-imidazol-2-yl)piperidin-l-yl)-
424
z. 5-methyl-5,6-dihydropyrido[2,3- L J ~z.~
d]pyrimidin-7(8H)-one N CH3
N"X^I
I X X
N NO
H
(R)-5-mcthyl-4-(4-(l-(2- K
(methylamino)ethyl)-4-
3 (trifluoromethyl)-lH-imidazol-2-
438

yl)piperidin-1 -yl)-5,6- L. J CH3 b
N CH

dihydropyrido[2,3-d]pyrimidin-7(8H)- N N ^0 H
one methanesulfonate


5-(4-(4-ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-lH-imidazol-2-yl)piperidin-l- VN^N\J
4 yl)-3-(2,2,2-trifluoroethyl)-3,4- f] F 507
dihydropyrimido[4,5-d]pyrimidin-2(lH)-one V F^ — F
K X X
H
F F F !=\
(R)-5-methyl-4-(4-(l-(2-(tert-pentylamino)ethyl)-4-(trifluoromethyl)- NTN\H3C>rcH3
/^\ N CH,
5 1 H-imidazol-2-yl)piperidin-1 -yl)-5,6- CJ H 494
dihydropyrido[2,3-d]pyrimidin-7(8H)- N CH3
one N NO
H

6 (R)-4-(4-(l-(2-
(cyclopropylmethylamino)ethyl)-4-
(trifluoromethyl)-1 H-imidazol-2-
yl)piperidin-l-yl)-5-methyl-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one N
4-(2,2,2-trifluoroethyI)-1 H-imidazoI-2-
yI)piperidin-l-yI)-5-(trifluoromethyI)-
5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one
NVN^H3C CH3 /L ^N CH,

H 548
37 (R)-4-(4-( 1 -(2-(tert-butyIamino)ethyI)-
4-(tetrahydro-2H-pyran-4-yI)-1H-
imidazoI-2-yI)piperidin-l-yI)-5-
(trifluoromethyl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one A. N CH-
!F F
N N ^0 H 550
38 (R)-4-(4-( 1 -(2-(tert-butylamino)ethyl)-
4-ethyI-1 H-imidazol-2-yl)piperidin-1 -
yl)-5-methyl-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one CH,
NyNV13c>/CH3

N CH3
N NO H 440

39
(R)-4-(4-(l-(2-(tert-butylamino)ethyl)-
4-cyclopropyl-1 H-imidazol-2-
yl)piperidin-1 -yl)-5-(trifluoromethyl)-
5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one NYN^H3C^CH3 /-k N CH„
(X H !F F
^X X
N N O H 506
40 (R)-4-(4-( 1 -(2-(^^-butylamino)ethyl)-4-isopropyl-1 H-imidazol-2-yl)piperidin-
1 -yl)-5-(trifluoromethyl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one CH3
NYNV)3C>/CH3
0 F s °"'
N f
KX x
N N 0 H 508
41 (R)-4-(4-(4-chloro-1 -(2-(pyrrolidin-1 -
yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -
yl)-5-methyl-5,6-dihydropyrido[2,3-
dJpyrimidin-7(8H)-one N CH3
N N^X) H 444
452
42 (R)-5-ethyl-4-(4-(4-ethyl-1 -(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-
yl)piperidin-1 -yl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one CH,
VNV^N\J
LNJ ^CH3
N N 0 H

43

(R)-4-(4-(l-(2-(tert-butylamino)ethyl>
4-cyclopropyl-1 H-imidazol-2-
yl)piperidin-1 -yl)-5-methyl-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-one dihydrochloride

J^ fj CH3 HCIHCI
N CH,

44

(R)-4-(4-(4-( 1 -methoxy-2-methylpropan-2-yl)-l-(2-(pyrro!idin-l yl)ethyl)-1 H-imidazol-2-yl)piperidin-1
yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

45

5-(4-(4-cyclopentyl-l-(2-(pyrrolidin-yl)ethyl)-1 H-imidazol-2-yl)piperidin-yl)-3-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(lH)-one

46

(R)-4-(4-(4-cyclopentyl-1 -(2-
(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-
yl)piperidin-1 -yl)-5-(trifluoromethyl)-
5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one

(R)-4-(4-(4-cyclohexyl-l-(2-(pyrroiidin-
47 1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin- 492
T^ / l-yl)-5-methyl-5,6-dihydropyrido[2,3-

d]pyrimidin-7(8H)-one
ChL
(R)-4-(4-(4-ethyl-1 -(2-(pyrrolidin-1 - f| \ / HCI HCI
yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -

48 yl)-5-(trifluoromethyl)-5,6-
492
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one dihydrochloride

(R)-5-methyl-4-(4-(4-(l-
methylcyclopropyl)-1 -(2-(pyrrolidin-1 -
49 yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 - 464
yl)-5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one

(R)-4-(4-( 1 -(2-(pyrrolidin-1 -yl)ethyl)-4-
(2,2,2-trifluoroethyl)-lH-imidazol-2-
50 yl)piperidin-1 -yl)-5-(trifluoromethyl)- 546
5,6-dihydropyrido[2,3-d]pyrimidin- lNJ F
7(8H)-one ' F-^F

1 "1 IN v-1
H

51 (R)-4-(4-( 1 -(2-(tert-butylamino)cthyl)-
4-isopropyl-1 H-imidazol-2-yl)piperidin-
l-yl)-5-methyl-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one dihydrochloride
52 (R)-4-(4-(4-isopropyl-l-(2-(isopropylamino)ethyl)-1 H-imidazol-2-
yl)piperidin-1 -yl)-5-methyl-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one dihydrochloride
53 (R)-4-(4-(4-cyclopropyl-1 -(2-
(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-
yl)piperidin-1 -yl)-5-(trifluoromethyl)-
5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one
54 (R)-4-(4-(4-cyclobutyl-l-(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-
l-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

454
440
504
464

55 (R)-4-(4-(4-isopropyl-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidin-
1 -yl)-5-(trifluoromethyl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one ,CH3
H3C y
F -[ F
KX X
N N ^0 H 506 479
56 (R)-4-(4-(4,5-dichloro-l-(2-(pyrrolidin-
1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-
l-yl)-5-methyl-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one CI CI
M
N CH3
N "l^l
N NO H

57 5-(4-(4-isopropyl-l-(2-(pyrrolidin-l-
yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -
yl)-3-(2,2,2-trifluoroethyl)-3,4-
dihydropyrimido[4,5-d]pyrimidin-
2(lH)-one /CH3
0 f
N F—h- F
KX xn
N NO
H 521
58 (R)-4-(4-( 1 -(2-(cyclobutylamino)ethyl)-
4-(trifluoromethyl)-1 H-imidazol-2-
yl)piperidin-l-yl)-5-methyl-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one F F
F )=\ NVN^
N CH3
N N ^0 H 478


488
59

(R)-4-(4-(4-bromo-1 -(2-(pyrrolidin-1 yl)ethyl)-1 H-imidazol-2-yl)piperidin-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

60

(R)-5-methyl-4-(4-( 1 -(2-(pyrrolidin-1 -
y l)ethyl)-4-vinyl-1 H-imidazol-2-
yl)piperidin-1 -yl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one

436

61

(R)-2-(l-(5-methyl-7-oxo-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-lH-imidazole-4-carbonitrile

435


62

(R)-4-(4-(4-cyclopentyl-1 -(2-(pyrrotidin-1 -yl)ethyl)-1 H-imidazol-2-
yl)piperidin-l-yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-
one

478

63

(R)-4-(4-(4-cyclopropyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-
yl)piperidin-1 -yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-
one

450

64

(R)-5-methyl-4-(4-( 1 -(2-(pyrrolidin-1 -yl)ethyl)-4-(2,2,2-trifluoroethyl)-1H-
imidazol-2-yl)piperidin-1 -yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-
one

492

65
(R)-4-(4-(4-ethyl-1 -(2-(pyrrolidin-1 -
yl)ethyl)-lH-imidazol-2-yl)piperidin-l-
yl)-5-methyl-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one ,CH3
N CH3
N NO H 438
66 (R)-4-(4-(4-tert-butyl-1 -(2-(pyrrolidin-
l-yl)ethyl)-lH-imidazol-2-yl)pipcridin-
l-yl)-5-methyl-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one 3 >^CH3

N CH3
N N ^0 H 466
67 (R)-4-(4-(4-isopropyl-l-(2-(pyrrolidin-
1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-
l-yl)-5-methyl-5,6-dihydropyrido[2,3-
d]pyrimidin-7(8H)-one CH3
H3C~N CH3
N N 0 H 452

68
(R)-4-(4-( 1 ~(2-(pyrrolidin-1 -yl)ethyl>4-
(tri fluoromethyl)-1 H-imidazol-2-
yl)piperidin-l-yl)-5-(trifluoromethyr)-
5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one N [
F~-rL~F
N N ^0 H 532
69 (R)-4-(4_(4_butyl-1 -(2-(pyrrol idin-1 -yl)ethyl)-lH-imidazol-2-yl)piperidin-l-
yl)-5-(trifluoromethyl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one ,CH3
N
N
(I
N N 0 H 520
70 (R)-4-(4-(4-propyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-lH-imidazol-2-yl)piperidin-l-
yl)-5-(trifluoromethyl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one 506



(R)-4-(4-(4-ethyl-1 -(2-(tetrahydro-2H-
pyran-4-ylamino)ethyl)-lH-imidazol-2-
71 yl)piperidin-1 -yl)-5-methyl-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one
(R)-4-(4-( 1 -(2-(pyrrolidin-1 -yl)ethyl)-4-
(tetrahydro-2H-pyran-4-yl)-l H-
72 imidazol-2-yl)piperidin-1 -yl)-5-ethyl-
5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one

468
508

Example 73
(R)-5-Methyl-4-(4-( 1 -(2-(pyrrolidin-l -yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-
imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8II)-onc

Charge 4-( 1 -(2-(Pyrrolidin-1 -yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-111-imidazol-2-yl)piperidine trihydrochloride (300 g, 1.0 equiv), (R)-4-Chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (146.2 g, 1.0 equiv) and n-propanol (3.0 L) to

a 12-L reaction flask. Stir the reaction mixture and add l,8-diazabicyclo[5.4.0] undcc-7-ene (394.3 g, 3.5 equiv) over ten minutes. Heat the reaction to 90 °C for 8 hours, and allow to cool to room temperature over 12 hours. Displace the n-propanol with n-butyl acetate to a total volume of 3-L and a residual n-propanol content of 11 % (w/w). Heat the organic solution to 50 - 60 °C and wash with brine (2.25 L). Back-extract the aqueous phase with nButyl acetate (1.5 L) and combine the organic layers. Wash the combined organic layers with water (2 x 450 mL) at 50-60 °C. Separate the organic layer and add activated charcoal (75 g, 0.25 equiv) and stir at 50-60 °C for 30 min. Filter the slurry and rinse the solids with n butyl acetate (1.5 L). Wash with water (1 L), separate the organic phase and azeotropically dry the organic phase to remove water. At 50-60 °C, add heptanes (3.0 L) cool to 40 °C and add seed crystals. Allow the slurry to cool to room temperature over ~12 h. Cool to 0-5 °C, filter the slurry and wash with heptanes (2x900 mL). Dry in vacuo and isolate (R)-5-Methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5,6-dihydropyrido| 23-d]pyrimidin-7(8H)-one as a white solid (365.3 gs 64%). MS (ES) m/z = 494 [M |*.
Examples 74 and 75
4-(4-( 1 -(2-(Pyrrolidin-1 -yl)ethyl)-4-(trifluoromethyl)-1 H~imidazol-2-yl)piperidin-1 -yl)-5-
(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin~7(8H)-onc
and
(R)-4-(4-( 1 -(2-(Pyrrolidin-1 -yl)ethyl)-4-(trifluoromcthyl)-1 H-imidazol-2-yl)pipcridin-1 -
yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-dJpyrimidin-7(8H)-one


Combine 4-chloro-8-(2,4-dimethoxybenzyl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.65 g, 1.62 mmol), 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)piperidine trihydrochloride (0.76 g. 1.1 eq), N-methylpyrrolidinone (20 mL) and diisopropylethylamine (1.69 mL, 6.0 eq) in a sealed vessel. Heat at 220°C for 30 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 1 -10% methanol/dichloromethanc gradient, to give crude 8-(2,4-dimethoxybenzyl)-4-(4-(l-(2-(pyrrolidin-l-yl)cthyl)-4-(trifluoromethyl)-1 H-imidazol-2~yl)piperidin-1 -yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (crude).
Combine the crude protected intermediate (1.10 g, theoretical) and trifluoroacctic acid (5.00 mL, 41 eq) in a microwave tube. Seal the tube and heat in a microwave reactor at 100°C for ten minutes. Concentrate in vacuo. Dilute the reaction mixture with water and extract with ethyl acetate. Wash the organics with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 5-20% methanol/dichloromethane gradient, to give 4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3 -d]pyrimidin-7(8II)-one as a racemate (0.70 g, 82%). MS (ES) m/z = 532 [Mf.
Chiral separation (Chiralpak AD-H, 30% ethanol/70% C02 w/ 0.2% isopropylamine) provides enantiomer 1 (>99% ee) and (R)-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)piperidin-l-yl)-5-(trifluoromcthyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as enantiomer 2 (>99 % ee). MS (ES) m/z -----532 [M]+ for both compounds.
Examples 76 and 77
5-Methyl-4-(4-( 1 -(2-(pyrrolidin-1 -yl)ethyl)-4-(trifluoromethyl)-1 H-imidazol-2-
yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8II)-one
and

(R)-5-Methyl-4-(4-(l-(2-(pyrroH
yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

Add 4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.22 g, 1.11 mmol), 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)piperidine trihydrochloride (0.57 g, 1.2 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (1.16 mL, 6.0 eq) in a microwave tube. Seal the tube and heat in a microwave reactor at 200°C for 30 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with a 1-10% methanol/dichloromcthane gradient, to give 5-methyl-4-(4-( 1 -(2-(pyrrolidin-1 -yl)ethyl)-4-(trifluoromethyl)-1 H-imidazol-2-yl)piperidin-t-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as a racematc (0.19 g, 36%). MS (ES) m/z = 478 [M]+. Chiral separation (Chiralpak AD-H, 30% ethanol/70% CO2 w/ 0.2% isopropylamine) provides enantiomer 1 (>99% ee) and (R)-5-methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as enantiomer 2 (>99 % ee). MS (ES) m/z ~ 478 [M]+ for both compounds.
Example 78
(R)-5-Methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(trifluoromethyl)-lII-imida/ol-2-
yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8II)-onc


Add (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8II)-one (28.30 g, 143.20 mmol), 4-(4-trifluoromethyl-l-(2-(pyrrolidin-l-yl)ethyl)-lM-imida/ol-2-yl)piperidine (49.83 g, 1.10 eq) and triethylamine (43.47 g, 3.0 eq) in N-methylpyrrolidinone (86 mL). Heat the reaction mixture to 130°C. Cool the reaction mixture to room temperature after 2 hours. Pour the reaction mixture over ice/water (500 mL) with stirring. Extract with ethyl acetate (4x200 mL). Wash the organics with saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate and concentrate in vacuo. Suspend the solid in hexanes and stir for 30 minutes. Filter and dry under vacuum. Add 75% methyl tert-butyl ether in hexanes (800 mL) and heat to reflux. Cool the mixture to room temperature. Filter, wash with 75% methyl te/Y-butyl ether in hexanes (200 mL), and dry under vacuum at 40°C to give the title compound (48.00 g, 70%). MS (ES) m/z = 478 [M]+.
Example 79
(R)-4-(4-(4-Ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-
methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride


HCI

Add 4 M hydrochloric acid in dioxane (28.57 uL, 1.0 eq) to a solution of (R)-4-(4-(4-ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-mcthyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (50.00 mg, 0.11 mmol) in dicholoromcthanc (1 mL) at room temperature and stir for 15 minutes. Concentrate in vacuo to give the title compound (54.00 mg, 100%). MS (ES) m/z = 438 [M]+.
Prepare the following compounds essentially as described for (R)-4-(4-(4-cthyl-(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one hydrochloride:

MS
Ex Compound Name Structure (ES) m/z |M|+
CH3
H3C^
80 (R)-4-(4-(4-isopropyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-
l-yl)-5-(trifluorornethyl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one hydrochloride 1 V-V} HC, 506
i X X
N NO H


(R)-4-(4-( 1 -(2-(pyrrolidin-1 -yl)ethyl)-4-
(trifluoromethyl)-lH-imidazol-2-
yl)piperidin-l-yl)-5-(trifluoromethyl)-
5,6-dihydropyrido[2,3-d]pyrimidin-
7(8H)-one hydrochloride

HCI
532

82

(R)-4-(4-(4-trifluoromethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-
yl)piperidin-l-yl)-5-methyl-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-
one hydrochloride

N N 0
H

HCI

478

Example 83
(R)-4-(4-( 1 -(2-(terNButylamino)ethyl)-4-ethyl-1 H-imidazol-2-yl)piperidin-1 -yl)-5-
(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-onc
H3CXCH3 CH.
CH.

Combine tert-butyl 4-(l-(2-(tert'-butylamino)ethyl)-4-ethyl-1 H-imidazol-2-yl)piperidine-l-carboxylate (440.00 mg, 1.16 mmol), dichloromethane (20 mL). methanol (8 mL), and 4 M hydrochloric acid in dioxane (3.00 mL, 12.0 eq) under nitrogen and let

stir at room temperature overnight. Concentrate in vacuo to give 300 mg N-[2-|4-ethyl-2-(4-piperidyl)imidazol-l-yl]ethyl]-2-methyl-propan-2-amine. Combine this amine with (R)-4-chloro-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (300.00 mg, 1.0 eq) in N-methylpyrrolidinone (10 mL) and add diisopropylethylamine (1.66 mL, 8.0 eq). Seal with crimp cap. Heat in a microwave reactor at 200°C for 40 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to ethyl acetate to 5% methanol/ethyl acetate to 3% to 5% to 7% to 10% methanol/dichloromethane, to give the title compound (0.08 g, 14%). MS (ES) m/z -- 494 [M]+.
Prepare the following compounds essentially as described for (R)-4-(4-(l-(2-(/ wet, 0.1 g/g limiting reagent) to a solution of terr-butyl 4-[4-(3,6-dihydro-2H-pyran-4-yl)-l -(2-pyrrolidin-1 -ylethyl)imidazol-2-yl]piperidine-l-carboxylate (30 g, 69.67 mmol) in ethanol (210 mL). Stir under a hydrogen atmosphere in a Parr system (200 psi, 65-70°C) for 27 hours. Add additional palladium on charcoal (0.6 g, 50%> wet, 0.02 g/g limiting reagent) and stir under a hydrogen atmosphere in a Parr system (200 psi, 65-70°C) for five hours. Filter over Celite® and wash with ethanol. Concentrate the filtrate in vacuo and dissolve the residue in ethanol (150 mL). Add palladium on charcoal (0.6 g, 50% wet, 0.02 g/g limiting reagent) and stir under a hydrogen atmosphere in a Parr system (250 psi, 70°C) for 16 hours. Filter over Celite® and wash with ethanol. Concentrate the filtrate in vacuo to give tert~butyl4-[l-(2-pyrrolidin-1-ylethyl)-4-tetrahydropyran-4-yl-imidazol-2-yllpiperidine-1 -carboxylate as a brown oil (29.5 g, 98%). MS (ES) m/z = 433 [Ml*.

k. 4-[ 1 -(2-pyrrolidin-1 -yI-ethyI)-4-(tetrahydro-pyran-4-yl)-1 H-imidazoI-2-yI"|-piperidine:
Add aqueous 35% hydrochloric acid (23.20 mL, 4.7 eq) to a solution of te/7-butyl 4-[l-(2-pyrroIidin-l-yIethyl)-4-tetrahydropyran-4-yl-imidazol-2-yI]piperidine-l-carboxylate (29.0 g, 60.33 mmol) in isopropyl alcohol (120 mL). Stir at 50°C for six hours. Concentrate in vacuo. Add water (1 L) and 2 M aqueous sodium hydroxide to adjust the pH to 12. Extract with ethyl acetate (3 x 200 mL) and dichloromethane (3 x 200 mL). Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give 4-(4-(tetrahydro-2H-pyran-4-yl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine (21.5 g, 100%). MS (ES) m/z = 333 [M]+.
1. (R)-5-methyI-4-(4-(l-(2-(pyrroIidin-l-yI)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lII-imidazol-2-yI)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-onc: Combine (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8M)-one (15.69 g, 1.2 eq), triethylamine (10.14 mL, 1.1 eq), 4-[ 1 -(2-pyrrolidin-1 -yI-cthyl)-4-(tetrahydro-pyran-4-yl)-lH-imidazol-2-yI]-piperidine (22 g, 66.17 mmol) and N-methylpyrrolidinone (66 mL). Stir at 110°C for 16 hours, then allow to cool to room temperature. Dilute with ethyl acetate (110 mL) and water (220 mL). Add 5 M aqueous sodium hydroxide to adjust the pH to 12. Extract with ethyl acetate (2 x 200 mL). Wash the organics with saturated aqueous sodium chloride. Add water (220 mL) to the organics and aqueous 85% phosphoric acid to adjust the pH to 3. Wash the resulting acidic aqueous layer with ethyl acetate (2 x 100 mL). Add 5 M aqueous sodium hydroxide to adjust the pH to 12. Extract with ethyl acetate (3 x 70 mL). Wash the organics with saturated aqueous sodium chloride (50 mL). Dry the organics over anhydrous magnesium sulfate and concentrate in vacuo to give the final compound as a light brown solid (21.5 g, 64%). MS (ES) m/z = 494 [M]+.
Example 95
(R)-5-MethyI-4-(4-( 1 -(2-(pyrroIidin-1 -yI)ethyl)-4-(tctrahydro-2H-pyran-4-yl)- III-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one
Crystalline Form III

Approximately 100 mg of amorphous (R)-5-Methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one is added to a small vial and mixed with 5 mL of isopropyl ether and 100 u.L of butyl butyrate. A slurry of solid results. Crystalline seeds are added and the sample is slurried at room temperature and 1000 rpm overnight on the stirplate. A thick slurry of white solid results. The white solid is isolated by vacuum filtration and placed in a 65°C vacuum oven to dry.
X-Ray Powder Diffraction: The XRD patterns of the crystals are obtained on a Bruker D8 Advance X-ray powder diffractometer, equipped with a CuKa source k ^ 1.54056 A) and a Vantec detector, operating at 50 kV and 40 mA. Each sample is scanned between 4 and 40° in 29, with a step size of 0.02° in 29 and a scan rate of 9.0 seconds/step, and with 1 mm divergence and receiving slits and a 0.1 mm detector slit. The dry powder is packed into recessed top-loading sample holder and a smooth surface is obtained using a glass slide. The crystal form diffraction patterns are collected at ambient temperature and relative humidity.
It is well known in the crystallography art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions oi the polymorph are unchanged. See, e.g., The United States Pharmacopeia #23, National Formulary #18, pages 1843-1844, 1995. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature or humidity at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of ± 0.1 in 29 will take into account these potential variations without hindering the unequivocal identification of the indicated crystal form.
Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks (in units of ° 29), typically the more prominent peaks. Thus, a prepared sample of (R)-5-Methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one crystalline form III is characterized by an XRD pattern using CuKa radiation as

having diffraction peaks (2-theta values) as described in Table 1 below, and in particular having peaks at 8.53 in combination with one or more of the peaks selected from the group consisting of 17.06, 7.97, and 14.17; with a tolerance for the diffraction angles of 0.1 degrees.
Table 1: X-ray powder diffraction peaks of (R)-5-Methyl-4-(4-(l-(2-(pyrrolidin-l-
yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-
dihydropyrido[2,3-d]pyrimidin-7(8H)-one crystalline form III.

Peak Angles (+/- 0.1 °2-Theta) Rel. Intensity (% of main peak)
7.97 52
8.53 100
14.17 57
15.97 27
16.56 32
17.06 97
17.81 57
19.03 25
19.36 26
21.73 34
10 Example 96
(R)-4-(4-(l-(2-(Azetidin-l-yl^
l-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-onc

N N O H
a. Methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4,4-trifluorobutanoate;

Heat a solution of 25% sodium methoxide in methanol (1.49 L, 0.86 eq) at 62°C. Add a mixture of propanedioic acid dimethyl ester (1.00 kg, 7.57 mol) and ethyl 4,4,4-trifluorocrotonate (1.27 kg, 1.0 eq) dropwise over two hours. Heat the mixture at 62°C for two hours. Cool the mixture to 30°C. Add 25% sodium methoxide in methanol (2.34 L, 1.35 eq) and formamidine acetate (867.2 g, 1.1 eq). Stir at 30°C overnight. Cool the mixture to 0°C and add 5 M aqueous hydrochloric acid, adjusting the pH to 4.5. Filter and wash with water (2 L). To the wet solid, add methyl tert-butyl ether (5 L). Filter, wash with additional methyl tert-b\ity\ ether (2 L), and dry at 50 °C to give methyl 3-(4,6-dihydroxypyrimidin-5-yl)-4,4,4-trifluorobutanoate (1.05 kg, 52%).
b. Methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoate:
Cool phosphoryl chloride (3.15 L, 8.6 eq) to 0°C. Add methyl 3-(4,6-
dihydroxypyrimidin-5-yl)-4,4,4-trifluorobutanoate (1.05 kg, 3.94 mol) dropwise. Add N,N-diethylaniline (0.69 L, 1.1 eq) dropwise over one hour. Warm the mixture slowly to 100°C and heat overnight. Cool the mixture to room temperature and concentrate in vacuo. Dilute with acetonitrile (4 L) and add dropwise to a solution of potassium phosphate dibasic 3 M aqueous solution (6.86 kg, 10 eq), previously cooled to -2°C. Filter and wash the unwanted solids with dichloromethane. Separate the layers of the filtrate. Wash the aqueous phase with additional dichloromethane. Wash the organics with 2 M aqueous hydrochloric acid, water, and aqueous saturated sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoate (1.15 kg, 97%).
c. (R)-4-Chloro-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-onc:
Combine methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoate (501.0 g,
1.57 mol) and 2 M ammonia in isopropyl alcohol (1.57 L, 2.0 eq) in a pressure reactor. Heat at 120°C for seven hours. Cool the mixture to room temperature, then concentrate in vacuo. Dilute with hexanes (1 L). Filter to give crude product. Triturate this solid with 10% isopropyl alcohol in water (600 mL) and water (1.3 L). Filter and dry at 70 °C to give 4-chloro-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-onc (328.9 g, 83%) as a racemate. MS (ES) m/z = 252 [M]+.
Chiral separation (Chiralpak AS, ethanol (0.2% dimethylethylamine)) provides (R)-4-chloro-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one as cnantiomer 2 (>99% ee). MS (ES) m/z = 252 [M]+.

d. tert-Butyl 4-(4-(2,2,2-trifluoroethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate:
Combine selenium dioxide (8.80 g, 79.32 mmol), 1,4-dioxane (50 mL), acetic acid
(2 mL), and water (2 mL). Heat to reflux under nitrogen, then slowly add 4,4,4-trifluorobutan-2-one (7.59 mL, 1.0 eq) dropwise. Heat at reflux under nitrogen for 15 hours, then let cool to room temperature. Filter the reaction mixture to give an orange-red filtrate. To a separate flask, add tert-butyl 4-formylpiperidine-l-carboxylate (16.92 g, 1.0 eq) and ammonium acetate (15.28 g, 2.5 eq) in methanol (125 mL). Add the filtrate dropwise via addition funnel. Stir overnight at room temperature under nitrogen. Concentrate to dryness in vacuo. Add water and make basic with 28% ammonium hydroxide in water. Extract with dichloromethane. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with hexanes to 10% methanol/dichloromethane, to give crude product as a yellow oil. Dilute with dichloromethane and saturated aqueous sodium bicarbonate. Separate the layers. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate in vacuo to give tert-butyl 4-(4-(2,2,2-trifluoroethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate as a yellow solid (16.38 g, 62%). MS (ES) m/z = 334 |M|e. tert-Butyl 4-(l-(2-(tetrahydro-2H-pyran-2-yloxy) ethyl)-4-(2,2,2-trifluoroethyl)-
lH-imidazol-2-yl) piperidine-1-carboxylate:
Combine tert-buXy\ 4-(4-(2,2,2-trifluoroethyl)-1 H-imidazol-2-yl)pipcridinc-1 -carboxylate (3.52 g, 10.56 mmol), potassium hydroxide (1.91 g, 3.2 eq) (freshly powdered) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.90 mL, 1.2 eq) in dimethyl sulfoxide (35 mL). Heat the reaction mixture at 50°C overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash with water followed by saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo.
Combine tert-bv\y\ 4-(4-(2,2,2-trifluoroethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate (4.34 g, 13.02 mmol), potassium hydroxide (2.33 g, 3.2 eq) (freshly powdered) and 2-(2-bromoethoxy)tetrahydro-2H-pyran (2.40 mL, 1.2 eq) in dimethyl sulfoxide (43 mL). Heat the reaction mixture at 50°C overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash with water followed by saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo.

Combine the two solids from the above reactions. Purify by silica gel chromatography, eluting with hexanes to 9:1 hexanes:ethyl acetate to 3:1 hcxancs:ethyl acetate to 1:1 hexanes:ethyl acetate to 1:3 hexanes:ethyl acetate to ethyl acetate, to give tert-butyl 4-( 1 -(2-(tetrahydro-2H-pyran-2-yIoxy) ethyI)-4-(2,2,2-trifluoroethyI)-1II-imidazoI-2-yI) piperidine-l-carboxylate (4.19 g, 30%). MS (ES) m/z = 462 [M]f. 2-(2-(Piperidin-4-yI)-4-(2,2,2-trifluoroethyI)-1 H-imidazoI-1 -yl)ethanoI
dihydrochloride:
Combine tert-butyl 4-(l-(2-(tetrahydro-2H-pyran-2-yIoxy) ethyI)-4-(2,2,2-trifluoroethyI)-lH-imidazoI-2-yI) piperidine-l-carboxylate (3.12 g, 6.76 mmol), dichloromethane (88 mL), and methanol (35 mL). Add hydrogen chloride (17.3 mL, 10.2 eq) (4 M in dioxane) slowly. Stir overnight under nitrogen. Concentrate in vacuo to give 2-(2-(piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-lH-imidazol-l-yl)ethanoI dihydrochloride (2.37 g, 100%). MS (ES) m/z = 278 [M]+.
g. (R)-4-(4-(l-(2-HydroxyethyI)-4-(2,2,2-trifluoroethyI)-lH-imidazol-2-yl)piperidin-
l-yI)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one:
Add (R)-4-chIoro-5-(trifluoromethyI)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.70 g, 2.78 mmol), 2-(2-(piperidin-4-yI)-4-(2,2,2-trifluoroethyI)-lH-imidazol-l-yl)ethanoI dihydrochloride (1.17 g, 1.2 eq), N-methylpyrroIidinone (10 mL) and diisopropylethylamine (2.20 mL, 5.7 eq) in a microwave tube. Seal with crimp cap. Heat in a microwave reactor at 150°C for one hour. Dilute the reaction mixture with saturated aqueous sodium bicarbonate and extract with ethyl acetate. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with 5% methanol/dichloromethane to 10% methanol/dichloromethane to 10% 2 M ammonia in methanol/dichloromethane, to give (R)-4-(4-(l-(2-hydroxyethyI)-4-(2,2,2-trifluoroethyI)-lH-imidazoI-2-yI)piperidin-l-yI)-5-(trifluoromethyI)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.93 g, 68%). MS (ES) m/z = 493 [Mf.
h. (R)-2-(2-(l-(7-Oxo-5-trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-
yI)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1 H-imidazoI-1 -yl)ethyl
methanesulfonate
Combine (R)-4-(4-( 1 -(2-hydroxyethyI)-4-(2,2,2-trifluoroethyI)-1 H-imidazoI-2-yI)piperidin-l-yI)-5-(trifluoromethyI)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.93

g, 1.88 mmol), dichloromethane (14 mL), and triethylamine (0.79 mL, 3.0 eq). Place under nitrogen and cool to 0°C. Add methanesulfonyl chloride (0.17 mL, 1.2 cq) dropwise. After 30 minutes, dilute with dichloromethane and quench with saturated aqueous sodium bicarbonate. Separate the layers. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo to give (R)-2-(2-(l-(7-oxo-5-trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-lH-imidazol-l-yl)ethyl methanesulfonate as a yellow solid (1.07 g, 96%). MS(ES)w/z = 571 [M]+.
i. (R)-4-(4-(l-(2-(Azetidin-l-yl)ethyl)-4-(2,2,2-trifluoroethyl)-lH-imidazol-2-
yl)piperidin-l-yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-
one:
Combine (R)-2-(2-(l-(7-oxo-5-trifluoromethyl-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-4-(2,2,2-trifluoroethyl)-1 H-imidazol-1 -yl)ethyl methanesulfonate (1.04 g, 1.82 mmol), dimethylformamide (9.3 mL), and azetidine (1.11 mL, 9.0 eq) under nitrogen. Heat the reaction mixture at 50°C overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash the organic layer with water. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with 10% methanol/dichloromethane to 10% 2 M ammonia in methanol/dichloromethane, to give the title compound, (R)-4-(4-(l-(2-(azetidin-1 -yl)ethyl)-4-(2,2,2-trifluoroethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-(trifluoromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one, as a white solid (0.49 g, 51%). MS(ES)m/z=532[M]Example 97
(R)-5-Methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(3,3,34rifluoropropyl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

F F F v—x
N CH3
N N^O H
a. (R)-4-Chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one:
Prepare according to steps a to e of Example 92.
b. 5,5,5-Trifluoropentanal:
Combine 3,3,3-triacetoxy-3-iodophthalide (17.91 gs 1.2 eq) and dichloromcthanc (95 mL). Add 5,5,5-trifluoro-l-pentanol (5.00 g, 35.18 mmol) in dichloromethane (238 mL) dropwise under nitrogen. After 4 hours, filter the reaction mixture through Cclitc ®. Concentrate the filtrate in vacuo; combine with 50 mL of dichloromethane and wash with 1:1 10% sodium thiosulphate:aqueous sodium hydroxide (IN). Dry the organics with anhydrous sodium sulfate, filter, and concentrate in vacuo to give 5,5,5-tritluoropentanal as a colorless oil (2.13 g, 43%). 'HNMR (400 MHz, DMSO-d6) 5 9.61 (s, 1H), 2.50 (m, 2H),2.21 (m,2H), 1.66 (m, 2H).
c. 5,5,5-Trifluoro-2-oxopentanal:
Combine 5,5,5-trifluoropentanal (2.01 g, 14.35 mmol), 1,4-dioxane (10 mL). selenium dioxide (1.62 g, 1.0 eq), water (0.51 mL), and acetic acid (0.69 mL). Heat the mixture at 90°C and stir overnight. Allow the reaction mixture to cool to room temperature. Filter, wash the solids with dioxane. Combine the filtrate and washings to give 5,5,5-trifluoro-2-oxopentanal (2.21 g, 100%). GCMS m/z - 154.
d. tert-B\xty\ 4-(4-(3,3,3-trifluoropropyl)-lH-imidazol-2-yl)piperidine-l-carboxylatc:
Combine 28% ammonium hydroxide in water (18.6 mL), tert-butyl 4-formylpiperidinc-l-
carboxylate (3.04 g, 14.25 mmol), and methanol (22.6 mL). Place under nitrogen and
cool to 0°C. Add 5,5,5-trifluoro-2-oxopentanal (2.21 g, 1.0 eq, as a solution in dioxane)
under nitrogen. Allow to warm to room temperature. Stir for two days. Concentrate/>?
vacuo and add ethyl acetate and saturated aqueous sodium chloride. Separate the layers.
Extract the aqueous layer further with 9:1 dichloromethane:isopropyl alcohol. Dry the

combined organic layers over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with hexanes to 1:1 hexanes:ethyl acetate to ethyl acetate, to give tert-butyl 4-(4-(3,3,3-trifluoropropyl)-lH-imidazol-2-yl)piperidine-1-carboxylate as a thick amber oil (2.32 g, 47%). MS (ES) m/z = 348 [MJ*.
e. tert-Butyl 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(3,3,3-trifluoropropyl)-lH-imidazol-2-
yl)piperidine-1 -carboxylate:
Combine tert-butyl 4-(4-(3,3,3-trifluoropropyl)-lH-imidazol-2-yl)piperidine-l-carboxylate (2.27 g, 6.53 mmol), potassium hydroxide (1.20 g, 3.3 eq) (freshly powdered), and l-(2-chloroethyl)pyrrolidine hydrochloride (1.34 g, 1.2 eq) in dimethyl sulfoxide (100 mL). Heat the reaction mixture at 50°C overnight, then allow to cool to room temperature. Dilute with ethyl acetate. Wash with water followed by saturated aqueous sodium chloride. Dry the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by silica gel chromatography, eluting with 4:1 dichloromethane:isopropyl alcohol, to give tert-butyl 4-(l-(2-(pyrrolidin-l-yl)elhyl)-4-(3,3,3-trifluoropropyl)-lH-imidazol-2-yl)piperidine-l-carboxylate as a thick yellow oil (0.73 g, 25%). MS (ES) m/z = 445 [M]+.
f. 4-(4-(3,3,3-Trifluoropropyl)-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-
yl)piperidine tris(2,2,2-trifluoroacetate):
Combine tert-butyl 4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(3,3,3-trifluoropropyl)-lII-imidazol-2-yl)piperidine-l-carboxylate (0.73 g, 1.64 mmol) and dichloromethane (16.2 mL). Place under nitrogen and cool to 0°C. Add trifluoroacetic acid (16.2 mL). After 1 hour, concentrate in vacuo to give 4-(4-(3,3,3-trifluoropropyl)-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidinetris(2,2,2-trifluoroacetate) (1.12 g, 100%). MS (ES) m/z = 345 [M]+.
g. (R)-5-Methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(3,3,3-triiluoropropyl)-lH-
imidazol-2-yl)piperidin-l-yI)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-onc:
Add (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (0.33 g.
1.66 mmol), 4-(4-(3,3,3-trifluoropropyl)-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine tris(2,2,2-trifluoroacetate) (1.12 g, 1.0 eq), N-methylpyrrolidinone (10 mL) and diisopropylethylamine (2.30 mL, 8.0 eq) in a microwave tube. Seal with crimp cap. Heat in a microwave reactor at 200°C for 10 minutes. Dilute the reaction mixture with water and extract with ethyl acetate. Wash with saturated aqueous sodium chloride. Dry

the organics over anhydrous sodium sulfate, filter, and concentrate in vacuo. Purify by normal phase chromatography, eluting with hexanes to 10% methanol/dichloromethane, to give the title compound, (R)-5-methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(3,3,3-trifluoropropyl)-lH-imidazol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one, as an amber solid (0.23 g, 27%). MS (ES) m/z = 506 [M]+.
Example 98
(R)-4-(4-(4-Ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-mcthyl-
5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one

a. (R)-4-Chloro-5-mehtyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8II)-one;
Prepare according to steps a to e of Example 92.
b. tert-Butyl 4-(lH-imidazol-2-yl)piperidine-l-carboxylate:
Combine 28% ammonium hydroxide in water (373 mL), tert-butyl4-
15 formylpiperidine-1-carboxylate (127.00 g, 595.47 mmol), and methanol (508 mL). Stir al room temperature. After 15 minutes, add ethanedial (86.30 mL, 1.0 eq) (6.9 M in water) under nitrogen. After one hour, add water (1.14 L) dropwise over 45 minutes. Stir the resulting suspension overnight at room temperature. Filter and dry the resulting white solid under vacuum to give tert-butyl4-(lH-imidazol-2-yl)piperidine-l-carboxylale
20 (128.00 g, 86%). MS (ES) m/z = 252 [M]+.
c. tert-Butyl 4-(4,5-diiodo-lH-imidazol-2-yl)piperidine-l-carboxylatc:
Combine tert-butyl4-(lH-imidazol-2-yl)piperidine-l-carboxylate (50.00 g,
198.94 mmol) and dimethyl sulfoxide (200 mL). Add iodine (104.03 g, 2.1 eq) portionwise over 15 minutes. Heat the reaction mixture to 45°C under nitrogen. After 30

minutes, add potassium hydroxide (19.70 g, 1.5 eq). Allow to cool to room temperature and stir overnight. Add the reaction mixture slowly to aqueous sodium bisulfate (1.25 L, 1.65 wt%). Stir the resulting suspension for 45 minutes. Filter, wash with water, and dry the resulting solid to give /er?-butyl 4-(4,5-diiodo-lH-imidazol-2-yl)piperidine-l-earboxylate (98.00 g, 98%). MS (ES) m/z = 504 [M]+.
d. fer/-Butyl 4-(4,5-diiodo-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine-
1-carboxylate:
Combine tert-butyl 4-(4,5-diiodo-lH-imidazol-2-yl)piperidine-l-earboxylate (86.00 g, 170.93 mmol) and potassium hydroxide (45.13 g, 4.0 eq) inN-methylpyrrolidinone (258 mL), maintaining the temperature below 40°C. Stir at room temperature for 25 minutes, then add l-(2-chloroethyl)pyrrolidine hydrochloride (47.47 g. 1.6 eq). Heat the reaction mixture at 40°C overnight, then allow to cool to room temperature.
Combine /erf-butyl 4-(4,5-diiodo-lH-imidazol-2-yl)piperidine-1-carboxylate (10.00 g, 19.88 mmol) and potassium hydroxide (5.25 g, 4.0 eq) in N-methylpyrrolidinone (30 mL). Stir at 40°C for 30 minutes, then add l-(2-chloroethyl)pyrrolidine hydrochloride (5.52 g, 1.6 eq). Heat the reaction mixture at 40°C overnight, then allow to cool to room temperature.
Combine the two reaction mixtures above. Add to water (3.36 L) and adjust the pi I of the resulting mixture with 15% aqueous phosphoric acid to 7.5-8.0. Stir the suspension at 0-5°C for one hour. Filter, wash with water, and dry the resulting solid under vacuum to give /erf-butyl 4-(4,5-diiodo-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -earboxylate (102.00 g, 89%). MS (ES) m/z = 601 [M]+.
e. tert-Butyl 4-(4-iodo-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -
earboxylate:
Combine tert-butyl 4-(4,5-diiodo-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine-1-carboxylate (51.00 g, 84.96 mmol) and 2-methyltetrahydrofuran (357 mL). Cool the reaction mixture to 0°C. Add 2 M isopropylmagnesium chloride in tetrahydrofuran (55.22 mL, 1.3 eq) dropwise over 45 minutes, maintaining the temperature below 5°C. Add saturated aqueous ammonium chloride. Separate the layers. Wash the aqueous phase with methyl fer?-butyl ether. Wash the organics with aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate, decolor

with charcoal, filter, and concentrate in vacuo to give tert-butyl 4-(4-iodo-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate as a yellow solid (39.50 g, 98%). MS (ES) m/z - 475 [M]+.
f. /erf-Butyl 4-(4-( 1 -hydroxyethyl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-111-imidazol-2-
yl)piperidine-l-carboxylate; phosphoric acid:
Combine terr-butyl 4-(4-iodo-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-l-carboxylate (40.00 g, 82.63 mmol) and tetrahydrofuran (600 ml.). Cool to -70°C under nitrogen. Add 2.5 M n-butyllithium in hexanes (67.76 mL, 2.1 eq) dropwise. Add acetaldehyde (23.22 mL, 5.0 eq) and stir for 15 minutes. Quench over aqueous saturated ammonium chloride (75 mL). Separate the layers. Wash the aqueous phase with methyl fer/-butyl ether. Wash the organics with water and aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo. Dissolve in ethanol. Add 85% aqueous phosphoric acid dropwise to achieve a suspension. Stir the mixture overnight at room temperature. Filter and dry the resulting off-white solid under vacuum to give tert-butyl 4-(4-( 1 -hydroxyethyl)-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidine-1 -carboxylate; phosphoric acid (28.00 g, 69%). MS (ES) m/z = 393 [M]+.
g. tert-Butyl 4-(4-ethyl-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidinc-l-
carboxylate; phosphoric acid:
Add palladium hydroxide on carbon (4.20 g, 60%> wet, 0.15 g/g limiting reagent) to a solution of tert-butyl 4-(4-(l-hydroxyethyl)-l-(2-(pyrrolidin-l-yl)ethyl)-lIl-imidazol-2-yl)piperidine-l-carboxylate; phosphoric acid (28.00 g, 57.08 mmol) in methanol (10 mL). Stir under a hydrogen atmosphere in a Parr system (150 psi, 60°C) for six days. Stir further under a hydrogen atmosphere in a Parr system (300 psi, 80°C) for seven days. Filter over Celite®. Concentrate the filtrate in vacuo and dilute with acetone (280 mL). Stir overnight at room temperature. Filter and dry the resulting white solid under vacuum to give /erf-butyl 4-(4-ethyl-l-(2-(pyrrolidin-l-yl)ethyl)-lII-imidazol-2-yl)piperidine-l-carboxylate; phosphoric acid (23.00 g, 85%). MS (ES) m/z - 377 \M\+. h. 4-(4-Ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-lH-imidazol-2-yl)piperidine:
Combine terr-butyl 4-(4-ethyl-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine-l-carboxylate; phosphoric acid (18.27 g, 38.50 mmol) and water (9.1 mL). Add 12 M hydrochloric acid in water (9.63 mL, 3.0 eq) dropwise and stir at room

temperature. After one hour, adjust the pH of the reaction mixture with 2 M aqueous sodium hydroxide to 10. Dilute with dichloromethane. Separate the layers. Wash the aqueous phase with dichloromethane. Wash the organics with aqueous saturated sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give 4-(4-ethyl-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine (7.70 g. 72%). MS(ES)m/z = 277[M]+.
i. (R)-4-(4-(4-Ethyl-l-(2-(pyrrolidin-l^
methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one:
Combine 4-(4-ethyl-l-(2-(pyrrolidin-l-yl)ethyl)-lH-imidazol-2-yl)piperidine (7.70 g, 27.86 mmol), (R)-4-chloro-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (6.06 g, 1.1 eq), N-methylpyrrolidinone (25.4 mL) and triethylamine (4.27 mL, 1.1 eq). Stir overnight at 110°C under nitrogen, then let cool to room temperature. Dilute with ethyl acetate and water. Adjust the pH with 2 M aqueous sodium hydroxide to 10. Separate the layers. Wash the aqueous phase with ethyl acetate. Wash the organics with aqueous saturated sodium chloride. Concentrate the organics in vacuo. Dilute with ethyl acetate and water. Adjust the pH to 5. Separate the layers; discard the organic layer. Adjust the pH of the aqueous phase with 2 M aqueous sodium hydroxide to 11. Wash the aqueous phase with ethyl acetate. Wash the organics with water and aqueous saturated sodium chloride. Concentrate the organics in vacuo. Dilute with 2-methyltetrahydrofuran:hexanes (15:85, 77 mL). Stir overnight at room temperature. Filter and dry the resulting white solid under vacuum to give the title compound, (R)-4-(4-(4-ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5-methyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one (7.90 g, 65%). MS (ES) m/z = 438 [M|+.
Formulation Examples
Mannitol Formulation
The compound of Example 73 (500 mg) and Mannitol (500 mg) are combined and blended dry for 2 hours or until a homogenous mixture is formed. A defined quantity of the blend (184.54 mg; equivalent to 92.29 mg of the compound of Example 73) is weighed by hand into a hard gelatin capsule shell bottom and the upper capsule shell combined to enclose the blend. As an alternative, the blend of the compound of the

invention and Mannitol may be transferred into hard gelatin capsules using equipment such as the Xcelodose®S precision powder micro-dosing system and sealing machine.
PEG400 Formulation
The compound of Example 73 (126 mg) and PEG400 (621.5 mg) are combined in a container and heated to 70°C using a stirrer at 250 rpm for two hours or until the compound of Example 73 is completely dissolved. A defined quantity of the blend is weighed by hand or via an automated system into a soft gelatin capsule shell bottom and the upper capsule shell combined to enclose the capsule.
AKT1 In Vitro Enzyme Assay
Compound IC50 values against AKT1 target are determined using the AKT1 Transcreener™ Kinase ADP-FP Assay. This assay assesses the activity of AKT1 in the presence of compound inhibitors by measuring the concentration of adenosine diphosphate (ADP) formed in a kinase reaction. The kinase reactions (25 uL reaction volumes) are performed in 96-well half-area black polystyrene plates. Adenosine triphosphate (ATP) is added to start the reactions. Final reaction conditions are 56 millimolarN-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) pH 7.4, 0.008% TRITON™ X-100, 5 millimolar magnesium chloride, 30 micromolar Crosstidc peptide, 20 micromolar ATP, hAKTl Human Recombinant, V-AKT Murine Thymoma Viral Oncogene Homolog 1, histidine-tagged, expressed in insect cells, 4% dimethylsulfoxide and serial dilutions of compound (diluted 1:3 from 20,000 to 1 nanomolar). Following ATP addition, the reactions are incubated at room temperature for 60 minutes and then quenched with the addition of 25 u.L of a quench detection reagent containing 52 millimolar HEPES pH 7.5, 20 millimolar ethylenediaminetetraacetic acid (EDTA), 0.4 molar sodium chloride, 0.02% BRIJ-35™, 10 microgram/milliliter anti-ADP antibody, and 4 nanomolar ADP Far Red Tracer. Quenched reactions are incubated for 4-16 hours, and then read in a Tecan Ultra Evolution plate reader in Fluorescence Polarization mode using polarizing filters of Exeunm and EiT^nm wavelength. Millipolarization (mP) raw data is converted to micromolar ADP using a prepared ADP/ATP standard curve (Huss et al, Development of a Transcreener™ Kinase Assay for Protein Kinase A and Demonstration of Concordance of Data with a Filter-Binding Assay

Format, Journal of Biomolecular Screening, 12(4); 2007, 578-584). The IC50 value for each compound is derived using percent inhibition data which is calculated using the micromolar ADP reaction data relative to on-plate controls (active enzyme versus 100 millimolar inhibited enzyme controls). The percent inhibition and ten-point compound concentration data is then fit to a four-parameter logistic equation using ACTIVITYBASE 4.0 (Assay Guidance Manual Version 5.0, 2008, Eli Lilly and Company and NIH Chemical Genomics Center).
Example 41 was tested essentially as described above and was found to have an IC50 of 0.017uM. This demonstrates that Example 41 is active as an AKT1 inhibitor.
AlphaScreen SureFire Detection phosphorylated GSK3P (S9) in U87MG Cells
The effect of compounds on the formation of endogenous phosphorylated GSK3P serine 9 (pGSK3P) are measured using the AlphaScreen SureFire ® for pGSK3P(TGRGBS10K). □ □ DThis is a homogeneous assay format using immuno-sandwich capture of the phosphorylated analyte followed by detection using antibody-coated Alphascreen beads to generate an amplified signal.
U87MG cells are maintained in U87MG growth medium consisting of DMEM supplemented with 10% Fetal bovine serum, 1% Nonessential amino acids and 1% sodium pyruvate. For the assay, cells are harvested by standard procedures and then counted using Vi-Cell. Cells (50,000/well) are plated in 100 JIL of U87MG growth medium into Costar #3596 96 well plates. Plates are incubated overnight at 37°C, 5% C02.
On the day of the assay, cells are treated with 20 (.iL/well compound diluted in media containing 6% dimethylsulfoxide. After 1 hour at 37°C, the medium is removed and 50 JAL of SureFire Lysis Buffer (TGR Biosciences SureFire ® Kit component) is added per well and incubation continued at room temperature for 10 minutes with gentle shaking. The lysate (6.0 uL) is transferred to a 384 well ProxiPlate™ (Perkin Elmer #6006280). A mixture containing 0.96 JAL nactivation buffer, 0.19 (.iL each donor and acceptor beads, and 8.7|_iL Reaction Buffer for pGSK3p Dassay (TGR Biosciences, TGRGBS10K) is added to each well. The plate is sealed with foil, incubated at room temperature for 4 hours with gentle shaking and then read on Perkin Elmer EnVision

equipped with a TurboModule using standard AlphaScreen® settings (Ex680nm and Krr^o-620nm)- The percent inhibition determined from controls on each plate and ten-point compound concentration data are then fit to a four-parameter logistic equation using ACTIVITYBASE 4.0 (Assay Guidance Manual Version 5.0, 2008, Eli Lilly and Company and NIH Chemical Genomics Center).
All the exemplified compounds in which A is H or H have
been tested essentially as described above and have an IC50 of less than or equal to 2.8[iM. Example 41 was tested essentially as described above and was found to have an IC50of 1.5uM.
This demonstrates the ability of compounds of the present invention to inhibit AKT activity.
Determination of AKT In Vivo Target Inhibition (IV)
In vivo target inhibition by a single IV injection:
Exponentially growing U87MG cells derived from a human glioblastoma arc implanted subcutaneously in the rear flank of athymic rats. When the tumors reach the size of 200-250 mm , compounds are administered to the animals by a single IV injection in a dose-response study or in a time-course study. At the end of each treatment, animals are asphyxiated with CO2. Tumors are harvested by surgical excision, quickly frozen in liquid nitrogen and stored at -80°C until analysis. Sera are prepared from blood harvested from the heart by cardiac puncture and stored at -80°C until analysis. Sample Analysis:
The AKT inhibitor is extracted from serum with acetonitrite/methanol and analyzed alongside an internal standard by LC/MS/MS. Compound serum exposure and the calculation of TME C50 (threshold mimimun effective concentration) in the case of dose response studies.
Tumors are homogenized in 2 volumes of a lysis buffer containing 25 mM Tris (pH 7.5), Roche complete protease inhibitors, and 1 mM vanadate with Powcrgen 125 homogenizer, then sequentially passed through an 18 gauge needle and a 23 gauge

needle. Soluble cytoplasmic extracts are collected from the supernatant fraction after the lysates are centrifuged for 30 minutes at 20,000 x g. Protein concentrations in the cytoplasmic extracts are determined with a BCA kit. Phospho-GSK3b (pGSK3b) in the soluble extracts is analyzed with the ELISA Kit. For each study, percent inhibitions are calculated relative to the vehicle control group and ANOVA analysis is performed using the JMP software package for the determination of statistical significance.
Example 78 was tested essentially as described above in the in-vivo target inhibition assay and was found to have the following activity:

IV Dose
(mpk) Post IV Dose (hr) p(S9)GSK
3|3 - % inhibition
20 4 48 (n=2)
This demonstrates the ability of Example 78 to inhibit AKT in vivo.
ROCK2 In Vitro Enzyme Assay
Compound IC50 values against ROCK2 kinase are determined using the ROCK2 Transcreener™ Kinase ADP-FP Assay. This assay assesses the activity of ROCK2 in the presence of compound inhibitors by measuring the concentration of ADP formed in a kinase reaction. The kinase reactions (25 \xL reaction volumes) are performed in 96-well half-area black polystyrene plates. Enzyme is added to start the reactions. Final reaction conditions are 20 millimolar 3-(N-Morpholino)-propanesulfonic acid pH 7.4, 4 millimolar beta-glycero-phosphate, 0.01% TRITON™ X-100, 5 millimolar magnesium chloride, 25 micromolar peptide substrate (sequence RFARKGSLRQKNV (SEQ ID NO:l)), 10 micromolar ATP, ROCK2 Human recombinant enzyme (residues 11-552, histidine -tagged, expressed in insect cells), 4% dimethysulfoxide and serial dilutions of compound (diluted 1:3 from 20,000 to 1 nanomolar). Following enzyme addition, the reactions are incubated at room temperature for 60 minutes and then stopped with the addition of 25 uL of a quench detection reagent containing 52 millimolar HEPES pH 7.5, 20 millimolar EDTA, 0.4 molar sodium chloride, 0.02% BRIJ-35™, 10 microgram/milliliter anti-ADP antibody, and 4 nanomolar ADP Far Red Tracer. Quenched reactions are incubated for 4-16 hours, and then read in a Tecan Ultra Evolution plate reader in Fluorescence

Polarization mode using polarizing filters of Ex6i2nm and Eni633nm wavelength. Millipolarization (mP) raw data was converted to micromolar ADP using an ADP/ATP standard curve (Huss et al, Development of a Transcreener™ Kinase Assay for Protein Kinase A and Demonstration of Concordance of Data with a Filter-Binding Assay Format, Journal of Biomolecular Screening, 12(4); 2007, 578-584). The IC50 value for each compound is derived using percent inhibition data which is calculated using the micromolar ADP reaction data relative to on-plate controls (active enzyme versus 100 millimolar EDTA-inhibited enzyme controls). The percent inhibition and ten-point compound concentration data was then fit to a four-parameter logistic equation using ACTIVITYBASE 4.0 (Assay Guidance Manual Version 5.0, 2008, Eli Lilly and Company and NIH Chemical Genomics Center).
All the exemplified compounds in which A is H or " have
been tested essentially as described above and have an IC50 of greater than or equal to 20uM. Example 41 was tested essentially as described above and was found to have an IC50 of greater than 20uM.
Preferred compounds of the invention have low ROCK2 activity.
Cell Proliferation and Combination Studies
The proliferation assay uses the CellTiter-Glo Luminescent Cell Viability Assay System (commercially available from Promega) to determine the cell number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells.
The cells are plated in 96-well plate at 2000 cells /well in volume of 50uL medium (DMEM, 10% FBS, 25 mM HEPES, 1.0 mM Sodium Pyruvate, and 0.1 mM Non Essential Amino Acids) except column 1 with medium only as blank control. The plates are incubated overnight at 37°C and 5%CC>2. On the next day, compound stocks are prepared at 40 mM in DMSO (500X) and serially diluted in DMSO in a 96-well round bottom polypropylene plate. Compounds are assayed at 10 concentrations in duplicate, 4 compounds per plate.

4(j.L of the serial DMSO dilutions are transferred to a 96 deep-well plate and lmL complete culture medium is added to create 2X stock for dosing. 50(.iL of each 2X dosing stock is gently transferred to the corresponding well of the cell plate resulting in a 0.2% DMSO concentration and a 100(j.L final volume. 50 mL medium are added to the Control columns (Column 12) and background columns (Column 1). Cells are incubated with compound for at 37°C, 5% C02 for 72 hr.
After incubation, 100(J.L of the pre-prepared CellTiter-Glo reagent (Promega. Cat: G7571) is added in each well and then the cells are homogenized by mixing on an orbital shaker for 2 min and incubated at RT for 10 minutes to allow luminescent signal stabilization. Luminescent raw data is recorded on Wallac Victor V plate reader and the IC50 value for each compound is generated using percent inhibition data. A four-parameter logistic curve is fit to each dose response.
Combination studies use the fixed ratio method, where the other therapeutic agent and the compound of the present invention are present in fixed ratios of concentrations corresponding to the IC50 equivalents of single agents. The read out for the combination studies is cell proliferation in respective cell lines using Cell Titer Glo reagents. Controls are processed similarly but without the compounds. Analysis of the data is done according to the method described in Zhao et. Al. (Clinical Cancer Research 10, 7994-8004, December 1, 2004) utilizing an internally developed web based tool. A combination index is calculated for each cell proliferation inhibition activity level according to the equation below.
Combination Index at activity level x =
[Concentration of other therapeutic agent in the combination at the activity level x/ICx o[ the other therapeutic agent] + [Concentration of the compound of the present invention in the combination at the activity level x/ICx of the compound of the present invention]
For clarity, Combination index values at 50% inhibition are summarized below.

Example Other Therapeutic
Agent Cell Line Combination Index at 50% Inhibition 95%
Confidence
Interval
77 Pemetrexed Calu6 0.93 0.68-1.24
77 Pemetrexed NCI-H1975 1.73 0.83-3.71
77 Cisplatin A2780 0.93 0.74-1.18
73 Cisplatin HI 155 0.82 0.62-1.10
77 Cisplatin Calu6 0.86 0.65-1.12
77 Cisplatin NCI-H1975 0.77 0.65-0.91
77 Cisplatin SK0V3 1.00 0.89-1.12
77 Cisplatin NCIH460 0.76 0.70-0.82
77 Cisplatin NCIH460 0.91 0.82-1.01
77 Docetaxel Calu6 0.65 0.54-0.77
77 Docetaxel NCIH460 0.82 0.76-0.88
77 Docetaxel NCI-H1975 1.13 0.91-1.37
77 Doxorubicin A2780 0.85 0.59-1.28
77 Doxorubicin SK0V3 1.12 0.96-1.30
77 Erlotinib H1155 0.16 0.03-0.40
77 Erlotinib H1155 0.73 0.58-0.92
73 Erlotinib H1155 0.38 0.31-0.46
73 Erlotinib H1155 0.77 0.58-1.03
77 Gemcitabine H1155 0.43 0.26-0.66
73 Gemcitabine H1155 0.87 0.70-1.08
77 Gemcitabine Calu6 1.16 0.60-2.02
77 Gemcitabine NCIH460 0.88 0.76-1.01
77 Gemcitabine NCI-H1975 0.55 0.29-0.87
77 Gemcitabine AsPCl 0.23 0.10-0.48
77 Gemcitabine BxPC3 1.13 0.69-1.94
77 Gemcitabine H1650 0.43 0.20-0.78
77 Gemcitabine HCC827 0.17 0.02-1.83
77 Gemcitabine MCF-7 0.10 0.02-0.33

Example Other Therapeutic
Agent Cell Line Combination Index at 50% Inhibition 95%
Confidence
Interval
77 Gemcitabine MDA-MB-231 0.39 0.13-2.18
77 Irinotecan RKO 0.83 0.71-0.96
73 Pemetrexed HI 155 0.29 0.13-1.52
77 Rapamycin AsPCl 0.22 0.08-0.50
77 Rapamycin BxPC3 0.15 0.06-0.33
77 Rapamycin MCF-7 0.46 0.30-0.75
77 Rapamycin HCC-827 1.13 0.22-7.57
77 Rapamycin HI 650 0.07 0.00-57.13
77 Rapamycin MDA-MB-231 0.01 0.00-0.10
77 Tamoxifen MCF-7 0.74 0.49-1.10
77 Erlotinib Calu6 0.20 0.11-0.41
77 Erlotinib NCIH460 0.64 0.57-0.71
77 Erlotinib NCI-H1975 0.47 0.39-0.55
77 Erlotinib AsPCl 0.23 0.11-0.42
77 Erlotinib BxPC3 0.36 0.22-0.56
77 Erlotinib H1650 0.04 0.01-0.11
77 Erlotinib HCC827 1.87 0.01-9.04
77 Erlotinib MCF-7 0.58 0.37-0.94
77 Erlotinib MDA-MB-231 0.05 0.01-0.90
77 Tasisulam Calu6 1.16 0.80-1.69
77 Paclitaxel MCF-7 0.60 0.44-0.83
73 Paclitaxel MCF-7 0.56 0.42-0.74
77 Paclitaxel MDA-MB-231 1.13 0.79-1.61
73 Paclitaxel MDA-MB-231 1.25 0.98-1.60
Determination of AKT In Vivo Target Inhibition (Oral and Parenteral)
U87MG human glioblastoma cells (5 x lOs) are subcutaneously implanted into the Hank of athymic nude mice in 0.2 mL of matrigel. Two weeks post-implantation, mice arc

dosed orally or parenterally according to a time course, single dose/single time point, or dose response protocol for the determination of TMED50 (threshold minimum effective dose). Tumors are flash frozen at harvest and blood is collected for the determination of parent compound plasma exposure and the calculation of TMEC50 (threshold minimum effective concentration) in the case of dose response studies. Tumors or tissues arc pulverized in liquid N2 and lysed in 400 \xL of XY Lysis Buffer (10 |ag/mL Leupeptin, 10 |ag/mL Trypsin-Chymotrypsin Inhibitor, 10 p.g/mL Tosyl phenyl-alanyl chloromcthyl ketone, 10 |ag/mL Aprotinin, 60 mM Beta-Glycerol Phosphate, 1% Triton XI00, 25 111M Tris pH 7.5, 2.5 mM Pyrophosphate, 150 mM NaCl, 2 mM p-tosyl-L-arginine methyl ester, 15 mM para-nitrophenyl phosphate, 5 mM Benzamidine, 1 mM Na Vanadate, 10 mMNaF, 50 |ig/mL phenyl-methane sulfonyl fluoride, 1 mM 1,4-Dithiothreitol (DTT). 15 mM EDTA pH 8.0, 5 mM EGTA pH 8.0, 1 uM Microcystin, 1 uM Okadaic Acid, and 1 Roche Complete protease inhibitor mini-tablet per 10 mL) using Lysing Matrix D tubes (MP Biomedicals, Solon, OH, cat# 6913-500) and a BIO101 Thermo Savant Fast Prep FP12. Lysates are aliquoted and either assayed immediately or stored at -80°C for later testing. In Vivo Target Inhibition of AKT is measured utilizing Meso Scale Discovery (Gaithersburg, MD) ELISA technology to assess effects on phosphorylation of the downstream effectors FOXO, PRAS40 and GSK3p(S9). In summary, 20 ng of lysatc is added to carbon electrode containing 96-well plates pre-spotted with the appropriate capture antibodies. The protein of interest is probed using a ruthenium labeled detection antibody. Upon the passage of current over the electrode in the presence of read buffer containing the co-reactant TPA, electro-chemiluminescence results in the generation of light which is quantified and recorded using the MSD Sector 6000 instrument. For each study, percent inhibitions are calculated relative to the vehicle control group and ANOVA analysis is performed using the JMP software package for the determination of statistical significance.
Example 26 was tested essentially as described above in the AKT in vivo target inhibition assay and was found to have the following activity after 2 hours at 12.5 mg/kg (mean of 6 animals per group):

Mean Plasma
Mean % Mean % Mean % Mean %
Glucose Inhibition Inhibition Inhibition Inhibition
(ng/ml) pGSK3p (S9) pAKT (S473) pPRAS40
(T246) FOX03a (T32)
234.7 34.4 21.7 8.1 36.8
This demonstrates the ability of Example 26 to inhibit AKT in vivo.

X18482_ST25 22 Sep 10 SEQUENCE LISTING
<110> Eli Lilly and Company
<120> AKT inhibitors
<130> x-18482
<150> 61/254308 <151> 2009-10-23
<160> 1
<170> patentin version 3.5
<210> 1
<211> 13
<212> PRT
<213> Artificial sequence
<220>
<223> Synthetic Construct
<400> 1
Arg Phe Ala Arg Lys Gly Ser Leu Arg Gin Lys Asn val
1 5 10

WE CLAIM:
1. A compound of the formula:

wherein: A is



or

R1 is CH3, CH2CH3 or CF3;
R2 is H, CF3, CH2CF3, CH2CH2CF3, CrC4 alkyl, C3-C6 cycloalkyl, CN, CI, Br, CH=CH2, CH2CH2OCH3, C(CH3)2CH2OCH3 or tetrahydropyran-4-yl, wherein C3-Q, cycloalkyl is optionally substituted by methyl at the 1-position and tetrahydropyran-4-yl is optionally substituted with methyl at the 4-position, and R3 is H;
or R2 and R3 are both CI;
R4 is H and R5 is CH3, C(CH3)3, CH(CH3)2, cyclobutyl, cyclopentyl, CH2-cyclopropyl, C(CH3)2CH2CH3 or tetrahydropyran-4-yl;
orR4andR5arebothCH3;
or R and R' together with the N to which they are attached form a pyrrolidine, optionally substituted by hydroxy at the 3-position, or an azetidine;
or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt
thereof, wherein A is:
R1
H
3. The compound according to claim 1 or claim 2, or a pharmaceutical ly acceptable salt thereof, wherein R is CH3 or CF3,
4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R2 is CF3, CH2CF3, CH2CH2CF3, CH2CH3, (CH2)2CH3, cyclopropyl, Br, CH2CH2OCH3 or tetrahydropyran-4-yl, and R3 is H.
5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R2 is CH2CF3, CH2CH2CF3 or CH2CH3 and R3 is H.
6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R4 is H and R5 is C(CH3)3; or R4 and R? together with the N to which they are attached form a pyrrolidine or an azetidine.
7. The compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together with the N to which they are attached form a pyrrolidine or an azetidine.
8. The compound according to claim 1 selected from: (R)-5-methyl-4-(4-(l-(2-(pyrrolidin-l-yl)ethyl)-4-(353,3-trifluoropropyl)-lH-imida/ol-2-yl)piperidin-l-yl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one;
(R)-4-(4-(4-ethyl-1 -(2-(pyrrolidin-1 -yl)ethyl)-1 H-imidazol-2-yl)piperidin-1 -yl)-5 -mcthyl-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one; and

(R)-4-(4-( 1 -(2-(azetidin-1 -yl)ethyl)-4-(2,2,2-triflouroethyl)-1 H-imidazol-2-yl)piperidin- ] -yl)-5-(triflouromethyl)-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-one, or pharmaceutically acceptable salts thereof.
9. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
10. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in therapy.
11. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, for use in the treatment of lung cancer, breast cancer or glioblastoma.

12. A method for treating lung cancer, breast cancer or glioblastoma in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof
13. A pharmaceutical composition for use in therapy comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition for treating lung cancer, breast cancer or glioblastoma comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier and optionally other therapeutic agents.