Bicyclic-fused heteroaryl or aryl compounds and their use as irak4 inhibitors

FUSIONED BICYCLIC HETEROARILO OR ARILO COMPOUNDS AND ITS USE AS IRAK4 INHIBITORS

FIELD OF THE INVENTION

The present invention relates to compounds useful for the treatment of autoimmune and inflammatory diseases associated to the kinase associated with the interleukin-1 (IR) receptor and, more particularly, to compounds that modulate the function of IRAK4.

BACKGROUND OF THE INVENTION

Protein kinases are families of enzymes that catalyze phosphorylation of specific residues in proteins, which are broadly classified into tyrosine and serine / threonine kinases. It is believed that the inappropriate activity that arises from the deregulation of certain kinases through a variety of mechanisms are the causes of many diseases, including, but not limited to, cancer, cardiovascular disease, allergies, asthma, respiratory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative diseases. As such, potent and selective kinase inhibitors are sought as possible treatments for different types of diseases in humans.

There is considerable interest in targeting the innate immune system in the treatment of immune diseases and sterile inflammation. The innate immune system receptors provide the first line of defense against bacterial and viral risks. These receptors recognize bacterial and viral products, as well as pro-inflammatory cytokines, and thus initiate a signaling cascade, which ultimately results in the up-regulation of inflammatory cytokines, such as TNFa, IL6 and interferons. It has recently become apparent that self-generated ligands, such as nucleic acids and inflammation products, such as high mobility group B1 protein (HMGB1) and advanced glycation end products (AGE) ssfh ligands for type receptors toll (TLR), which are the key receptors of the system (Innate immune system (O'Neill 2003, Kanzler et al 2007, Wagner 2006). This demonstrates the role of TLRs in the beginning and the durability of inflammation due to autoimmunity.

-1The kinase 4 associated with the interleukin 1 receptor (IRAK4) is a serine kinase // threonine that participates in the regulation of innate immunity (Suzuki & Saito 2006). IRAK4 is responsible for initiating signaling of TLRs and family members of the IL-1/18 receptor. It was reported that inactive kinase knock and directed elimination of IRAK4 in mice caused reductions in proinflammatory cytokines induced by IL-1 and TLR (Kawagoe et al 2007; Fraczek et al. 2008; Kim et al. 2007). Knock-in mice without IRAK4 kinase activity were also shown to be resistant to joint inflammation induced in serum-induced arthritis (K / BxN) and antigen-induced arthritis (ΑΙΑ) models (Koziczak-Holbro 2009). Similarly, humans with IRAK4 deficiency also appear to be unable to respond to the Toll and IL-1 Hgandos (Hernández & Bastían 2006). However, the immunodeficient phenotype of individuals with zero IRAK4 is narrowly restricted to the exposure of gram-positive bacteria, but not to gram-negative bacteria, viruses or fungi. This positive gram sensitivity is also reduced with age, which implies redundant or compensatory mechanisms for innate immunity in the absence of IRAK4 (Lavine et al 2007).

These data indicate that IRAK4 kinase activity inhibitors should have therapeutic value to treat autoimmune diseases driven by cytokine, while having minimal immunosuppressive side effects. Additional recent studies suggest that IRAK4 targeting may be useful in other inflammatory diseases, such as atherosclerosis and diffuse large B lymphocyte lymphoma (Rekhter et al 2008; Ngo et al 2011). Therefore, IRAK4 kinase activity inhibitors represent potential therapeutic measures for a wide variety of diseases, including, among others, autoimmune, inflammatory, cardiovascular, metabolic and cancer diseases. For more information see the following references: N. Suzuki and T. Saito, Trends in Immunology, 2006, 27, 566. T. Kawagoe, S. Sato, A. Jung, M. Yamamoto, K. Matsui, H. Kato, S. Uematsu, O. Takeuchi and S. Akira, Journal of Experimental Medicine, 2007, 204, 1013. J. Fraczek, TW Kim, H. Xiao, J. Yao, Q. Wen, Y. Li, J.-L. Casanova, J. Pryjma and X. Li , Journal of Biological! Chemistry, 2008, 283, 31697. TW Kim, K. Staschke, K. Bulek, J. Yao, K. Peters, KH. Oh, Y. Vandenburg, H. Xiao, W. Qian, T. Hamilton, B. Min, G. Sen, R. Gilmour and

-2X Li, Journal of Experimental Medicine, 2007, 204, 1025. M. Koziczak-Holbro, A. Littlewood-Evans, B. Pollinger, J. Kovarik, J. Dawson, G. Zenke, C. Burkhart, M. Muller and H Gram, Arthrítis & Rheumatism, 2009, 60, 1661. M. Hernández and JF Bastían, Current Allergy and Asthma Reports, 2006, 6, 468. E. Lavine, R. Somech, J.

Y. Zhang, A. Puel, X. Bossuyt, C. Picard, JL Casanova and CM Roifman, Journal of Allergy and Clinical Immunology, 2007, 120, 948. M. Rekhter, K. Staschke, T. Estridge, P. Rutherford , N. Jackson, D. Gifford-Moore, P. Foxworthy, C. Reidy, X.-d. Huang, M. Kalbfleisch, K. Huí, M.-S. Kuo, R. Gilmour and CJ Vlahos, Biochemical and Biophysical Research Communications, 2008, 367, 642. O'Neill, LA (2003). Therapeutic targeting of Toll-like receptors for inflammatory and infectious say. Curr Opin Pharmacol 3 (4): 396. Kanzler, H et al. (2007) "Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists." Nature Medicine 13: 552. Wagner, H. (2006) "Endogenous TLR ligands and autoimmunity" Advances in Immunol 91: 159. Ngo, VN et al. (2011) “Oncogenicaily active MyD88 mutations in human lymphoma” Nature 470: 115.

SUMMARY OF THE INVENTION The invention provides compounds of the Formula la,

<img file="CU20160149A7_D0001.tif" />

the where

X and X 'are, each independently, CR⁸, No N⁺-OR ~; And it is, independently, N, -N⁺-O'o CR⁸; provided that at least one of X, X 'or Y is not N or -N⁺-O ~ and that no more than one of X, X 'or Y is -N⁺-OR';

R¹ it is CrCealkyl; C2-C6alkenyl; C2-C6alkynyl; - (CR^3rdR^3b) m- (3- to 7-membered cycloalkyl); - (CR^3rdR^3b) m- (3 to 7-membered heterocycloalkyl) having 1 to 3 heteroatoms; - (CR^3rdR^3b) m- (5-10 membered heteroaryl), which has 1 to 3 heteroatoms; or - (CR^3rdR^3b)_m-C₆-C₁₂aryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl are substituted

-3 optionally with 1 to 5 halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11bcyano C_rC₆alkyl, C₃-C₆cycloalkyl or -C_rC₆alkoxy;

R² is - (CR^3rdR^3b) m- (3 to 10 membered cycloalkyl); - (CR^3rdR^3b) m (3-10 membered heterocycloalkyl) having 1 to 3 heteroatoms; (CR^3rdR^3b) m- (5-10 membered heteroaryl) having 1 to 3 heteroatoms; or (CR^3rdR^3b) mC₅-C₁₂aryl; wherein the cycloalkyl, heterocycloalkyl, heteroaryl or aryl are optionally substituted with 1 to 5 R⁴; and where, if the heteroatom in the heterocycloalkyl and heteroaryl is Ν, N is optionally substituted with R⁴; or R² it is CrCealquílo, where alkyl is optionally substituted with NH₂, OH or cyano;

p3a and p3b _SQnp_{arg cac}j_{to cgso} j_ncj_andp_encj¡_int_ernent_hey hydrogen or C_rC₃I rent;

R⁴ it is, for each case independently, a bond, deuterium, halogen, cyano, CrC6alkyl, C2-C6alkenyl, oxo, -OR⁵, -MR⁵, -S (O) R⁹, -S (O) 2R⁹, NR^11thR^11b, -C (O) R¹⁰, - (CR^3rdR^3b) n- (cycloalkyl of 3 to 7 members), - (CR^3rdR^3b) n (4-10 membered heterocycloalkyl), which has 1 to 3 heteroatoms, (CR^3rdR^3b) n- (5 to 10 membered heteroaryl), which has 1 to 3 heteroatoms, or (CR^3rdR^3b) n- C₆-C₁₂aryl wherein the alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl are each substituted independently and optionally with 1 to 5 deuterium, halogen, OR⁵, -MR⁵, -NR^11thR^11b, cyano, CrCealkyl, C3-C5cycloalkyl or CrCgalkoxy; or two R⁴, together with the respective carbons to which they are attached, form a 3-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11b, cyano or Cr C₆alkyl or Cf-Cealkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11b or cyano; and where, if a heteroatom in the heterocycloalkyl is N, N is optionally substituted with R⁴ ;

R⁴ is, independently, CT-Cealkyl, C2-C6alkenyl, -C (O) R¹⁰, S (O) 2R⁹, - (CR^3rdR^3b) n- (3-to 7-member cycloalkyl), - (CR^3rdR^3b) n (4-10 membered heterocycloalkyl) or C (O) (CH₂)_tCN; wherein the alkyl, alkenium, cycloalkyl or heterocycloalkyl are substituted, each independently and optionally, with 1 to 5 deuterium, halogen, OH, cyano or CrC₆alcox¡; or R⁴ and R⁴, together with the respective atoms to which they are attached, form a 3-6 membered cycloalkyl or a 4-6 heterocycloalkyl.

-4 members, where the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11bcyano C_rC₆alkyl or CrCealkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11b or cyano;

R⁵ is, independently, hydrogen or CrC6alkyl, where aiquiium is optionally substituted with halogen, deuterium, Ch-Cealcoxl, CrC6alkylolyl, NR^11thR^11b, cyano, C -, - Csalqu¡lo or C₃-C₆cycloalkyl; or two R⁵, together with the oxygen atoms to which they are attached, form a 5- or 6-membered heterocycloalkyl;

R⁶ is -C (O) NHR⁷, CO₂R⁷ or cyano;

R⁷ is hydrogen or C - C_and I rent;

every R⁸ is, independently, hydrogen, halogen, cyano, -OR⁵, -MR⁵, NR^11thR^11b, CrCealkyl, C3-Cecycloalkyl, 3-10 membered heterocycloalkyl or 5-6 membered heteroaryl or aryl, wherein alkyl, cycloalkyl, heterocycloalkyl, heteroaryl or aryl are optionally substituted with 1 to 3 halogen, -NR^11thR^11b, -OR⁵, -MR⁵, cyano, CrC₃ alkyl, -C (O) R¹⁰ or oxo;

R⁸ is hydrogen, deuterium, halogen, cyano, -OR⁵, -MR⁵ or NR^11thNR^11b;

R⁹ is - (CR ^ R ^ jp-ÍCrCsalquIlo), - (CR^3rdR^3b) p- (4 to 6-member group), - (CR^3rdR^3b) p- (4-6 membered heterocycloalkyl) or - (CR^3rdR^3b) p- (C₅-Cgaryl), wherein the alkyl, cycloalkyl, heterocycloalkyl or aryl are each optionally substituted with fluoro or Ci.C₃I rent;

R¹⁰ it's Ci-C₆alkullo, where alkyl is optionally substituted with deuterium, halogen, OH, CrC₆alkoxy or cyano;

R^11th and R^11b they are, each independently, hydrogen or Ct-C₆alkyl, wherein alkyl is optionally substituted with deuterium, C -, - C₅alkoxy or cyano; and in the case of C₂-C₆alkyl, this alkyl is optionally substituted with deuterium, C_rC₆alkoxy, cyano, halogen or OH;

m is independently 0, 1.2 or 3; n is, independently, 0, 1, 2 or 3; p is, independently, 0 or 1; and t is 1, 2 or 3;

or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

-5The invention also provides pharmaceutical compositions comprising the compounds, methods of use of the compounds, combined therapies using the compounds and other therapeutic agents and methods for preparing the compounds. The invention also provides intermediates useful for the preparation of the compounds of the invention.

In particular, the novel bicyclic enzyme kinase inhibitor compounds of Formula I of the present invention possess a therapeutic function of inhibiting IRAK4 useful in the area of ​​diseases and / or disorders that include, among others, different types of cancer, allergic diseases, autoimmune diseases, diseases and / or conditions and / or inflammatory disorders associated with inflammation and pain, proliferative diseases, hematopoietic disorders, hematological cancer, bone disorders, kidney disease, diseases and / or disorders due to fibrosis, metabolic disorders, diseases and / or muscle disorders, respiratory diseases, lung disorders, genetic development diseases, diseases and / or neurological and neurodegenerative disorders, inflammatory demyelinating neuropathies chronic, cardiovascular, vascular or cardiac diseases, ophthalmic / ocular diseases, scarring, infectious and viral diseases. Therefore, the inhibition of IRAK4 would have the potential for multiple therapeutic indications, with respect to a wide range of unmet needs.

DESCRIPTION OF THE FIGURES

Figure 1: Change of the average in the inflammation of the ears (pm) of the measurements of the ears at the beginning on day 5. Mice treated with Example 296 (PO BID daily X 5 days) and P40 Ab (IP day 1, 4) significantly reduced inflammation of the ears on the final day, compared to the vehicle (value p and%).

Figure 2: Figure 2. Volume of the delta legs in the collagen-induced arthritis model in rats with the use of Example 26.

-6 DETAILED DESCRIPTION OF THE INVENTION

The present invention can be more readily understood by reference to the following detailed description of exemplary embodiments of the invention and the examples included therein. It should be noted that the present invention is not limited to specific synthesis methods that, of course, may vary. Likewise, it should be noted that the terminology used herein is intended to describe only particular embodiments and is not intended to limit them.

Other features and advantages of the present invention will be apparent after analyzing this specification and the appended claims describing the invention. There are many features of this invention that are not necessarily fully captured by the claims. It is understood, however, that the novel object is part of the invention.

Definitions

Unless otherwise defined herein, the scientific and technical terms that are used with respect to the present invention will have the meaning usually granted to persons of the mid-level trade. As used in the specification and in the appended claims, the singular forms "a", "a" and "the" include the plural references, unless the context clearly indicates otherwise.

The term "around" refers to a relative term that denotes an approximation of plus or minus 10% of the nominal value to which it refers, in one embodiment, to more or less 5%, in another embodiment, to about 2%. For the field of this description, this level of approximation is adequate unless the value is specifically indicated to require a narrower range.

The term "alkyl" refers to a linoleum or branched saturated hydrocarbon portion, consisting solely of carbon and hydrogen atoms. In an embodiment of 1 to 6 carbon atoms; and in another embodiment of 1 to 4 carbon atoms; and in another embodiment of 1 to 3 carbon atoms. Examples of such substituents include methyl, ethyl, propyl (including, r? -Propyl and

-7isopropyl), butyl (including n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl, soamyl, hexyl and the like. As appropriate, an alkyl may optionally be substituted on each carbon as defined in the claims. Typical substitution includes, among others, fluoro, chloro, OH, cyano, alkyl (opclonally substituted), cycloalkyl and the like.

In some cases, the amount of carbon atoms in a hydrocarbon substituent (ie, alkyl, cycloalkyl, etc.) is indicated by the prefix "C_x-C_Y- ”or“ C_x._Y”, Where x is the minimum amount, e 'y' is the maximum amount of carbon atoms in the substituent. Accordingly, for example, "CrCs-alkyl" or "Crs alkyl" refers to an alkyl substituent containing 1 to 6 carbon atoms. In addition, C₃-C₆clcloalkyl or C3.₆-cycloalkyl refers to a saturated cycloalkyl containing from 3 to 6 carbon ring atoms.

Unless otherwise indicated, alqullen, by itself or as part of another term, refers to a cyclic or linear or branched chain saturated hydrocarbon dirradical of the amount of carbon atoms established, in general, 1-6 atoms carbon, and having two centers of monovalent radicals derived from the removal of two hydrogen atoms from those or two different carbon atoms from an alkane of origin. Typical alkylene radicals include, among others, methane (-CH₂-), 1,2-ethylene (-CH₂CH₂-), 2,2-dlmethylene, 1,3-propylene (-CH₂CH₂CH₂-),

2-Methyl Propylene, 1,4-Butlene (-CH₂CH₂CH₂CH₂-) and the like; optionally substituted, as appropriate, with 1 to 5 suitable substituents, as defined above, such as fluoro, chloro, deuteron, cyano, trifluoromethyl, (CrCejalcoxl, (C6-C₁₀) aryloxy, trifluoromethoxy, difluoromethoxy or (Cf-Cejalkyl. When the compounds of the invention contain a C ^ alkenyl group, the compound may exist as the pure E form (entgegen), the pure Z form (zusammen) or any mixture of these.

"Alqullldene" or "alkenyl" refers to a dlvalent group formed from an alkane by removing two hydrogen atoms from the same carbon atom, whose free valences are part of a double bond, optionally substituted as described herein. The term alqullldene also includes "alens, where in the carbon atom it has double bonds with each of its two adjacent carbon centers, such as propadlene. As appropriate, an alkenyl can be optionally substituted on each carbon, as defined in the

-8 claims, may optionally be substituted, as appropriate, with 1 to 5 suitable substituents as defined above and herein, such as fluoro, chloro, deutero, cyano, trifluoromethyl, (Ci-C₆) alkoxy, (C₆-C₁₀) arylox, trifluoromethoxy, difluoromethoxy or (C_rCe) alkyl.

The term "alkynyl" refers to an aliphatic hydrocarbon having at least one carbon-carbon triple bond, which includes cyclic, straight-chain or branched chain groups having at least one carbon-carbon triple bond, optionally substituted as described in ia Present. Preferably, it is a lower alkynyl having 2 to 6 carbon atoms. For example, as used herein, the expression C₂-₆"alkynyl" means a linear or branched hydrocarbon chain alkynyl radical, as defined above, having 2 to 6 carbon atoms and a triple bond. As appropriate, an alkynyl may optionally be substituted on each carbon as defined in the claims. Typical substitution includes, inter alia, optionally substituted, as appropriate, with 1 to 5 suitable substituents, as defined above and herein, such as fluoro, chloro, deutero, cyano, trifluoromethyl, (Ci-C₆) alkoxy, (C₆-C₁₀) aryloxy, trifluoromethoxy, difluoromethoxy or (CrC₀)I rent.

The term "cycloalkyl" refers to a non-aromatic ring containing 3 to 10 carbons that is completely hydrogenated and consisting of mono-, bi- or tricyclic rings. Consequently, a cycloalkyl can be a single ring which, in general, contains 3 to 7 ring atoms. Examples include, among others, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, 2 or 3 rings can be fused together, such as bicyclodecanyl and decalinyl. The term "cycloalkyl" also includes bridged bicycloalkyl systems, such as bicyclo [2.2.1] heptane and bicyclo [1.1.1] pentane. As described herein, the cycloalkyl group may optionally be substituted, as described herein, as appropriate, with 1 to 5 suitable substituents, as defined above, such as fluoro, chloro, deutero, cyano, trifluoromethyl, ( C₁-C₆) alkoxy, (C₆-C₁₀) arlox, trifluoromethoxy, difluoromethoxy or (CrCeJalkyl.

The term "heterocycloalkyl means a monovalent saturated portion, consisting of 1 to 3 rings and incorporating 1, 2, 3 or 4 heteroatoms (selected from N, O or S) and 3 to 10 carbon atoms. The heterocycloalkyl may be optionally substituted as defined herein. Portion Examples

-9heterocicloalquilo include, among others, piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pirrolldinilo, pirazolidinllo, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, tlazolidinilo, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolylidinyl, benzothiazolidinyl , benzoazolylidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorfilinylsulfone, dihydroquinolinyl, tetrahydroquinolinyl, optionally substituted tetrahydroquinolinyl, and the like. Heterocycloalkyl may optionally be substituted, as appropriate, with 1 to 5 suitable substituents, as defined herein, such as fluoro, chloro, deutero, cyano, trifluoromethyl, (Ci-C₆) alcox¡, (C₆-C₁₀) aryloxy, trifluoromethoxy, difluoromethoxy or (CrCgjalkyl.

Unless otherwise indicated, the term heteroalkyl, by itself or in combination with another term, means a saturated linear or branched chain hydrocarbon radical consisting of the amount of carbon atoms established and 1 to 3 heteroatoms selected from the group consisting of O, N and S, and wherein the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can optionally be quaternized. The heteroatoms of O, N and S can be placed in any interior position of the heteroalkyl group. Heteroatom S can be placed in any position of the heteroalkyl group, which includes the position in which the alkyl group binds to the rest of the molecule. Up to two heteroatoms can be consecutive.

Unless otherwise indicated, the term heteroalkylene, by itself or as part of another substituent, means a divalent group derived from heteroalkyl (as defined above). For heteroalkylene groups, heteroatoms can also occupy one or both terminals of the chain.

The terms "alkoxy" and "apyloxy," which may be used interchangeably, refer to a portion of the Formula -OR, wherein R is a saturated straight-chain alkyl or saturated branched-chain alkyl portion, as defined in the present, fixed through an oxygen atom. The alkoxy group may optionally be substituted as defined herein. Non-limiting examples of the alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy and the like.

-10 The term aryl ”means a carbocyclic aromatic system containing 1 or 2 rings, where the rings can be fused. If the rings merge, one of the rings must be totally unsaturated, and the fused rings can be fully saturated, partially unsaturated or totally unsaturated. The term "fused" means that there is a second ring (that is, attached or formed) that has two adjacent atoms in common (i.e., shared) with the first ring. The term merged is equivalent to the term condensed. The aryl group may optionally be substituted as defined herein. The term "aryl" embraces aromatic radicals, such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, benzo [b] [1,4joxazin-3 (4H) -onyl,

2,3-dihydro-1 H indenyl and 1,2,3,4-tetrahydronaphthalenyl. The rings may optionally be substituted, as appropriate, with 1 to 5 suitable substituents, as defined above, such as fluoro, chloro, deutero, cyano, trifluoromethyl, (C_rC_s) alcox¡, (C₆-C₁₀) arlox, trifluoromethoxy, difluoromethoxy or (Ci-C₆) rent it.

The term "heteroaryl" refers to an aromatic ring structure containing from 5 to 6 ring atoms, wherein at least one of the ring atoms is a heteroatom (i.e. oxygen, nitrogen or sulfur), and the remaining ring atoms they are independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. Examples of heteroaryl substituents include 6-membered ring substituents, such as pyridyl, pyrazyl, pyrimidinyl and pyridazinyl; and 5-membered ring substituents, such as triazolyl, midazolyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5 or

1,3,4-oxadiazolyl and isothiazolyl. In a group having a heteroaryl substituent, the heteroaryl substituent ring atom that is attached to the group may be one of the heteroatoms, or it may be a ring carbon atom. Similarly, if the heteroaryl substituent, in turn, is substituted with a group or substituent, the group or substituent can be attached to one of the heteroatoms, or it can be attached to a ring carbon atom. The term "heteroaryl" also includes pyridyl N-oxides and groups containing a pyridine N-oxide ring.

Other examples include furyl, thienyl, oxazolyl, thiazolyl, midazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolllo, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyridin-2 (1 F /) -inyl (1 / - /) - onyl, pyrimidin2 (1H) -on¡lo, pyrazin-2 (1 / - /) - onyl, imidazo [1,2-ajpyridinyl, pyrazolo [1,5-ajpyridinyl,

5,6,7,8-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroquinolinyl, 6,7-dihydro-5 / 7-11 cyclopenta [or] pyridinyl, 6,7-dihydro-5/7 -cyclopenta [c] pyridinyl, 1,4,5,6-tetrahydrocyclopenta [c] pyrazol, 2,4,5,6-tetrahydrocyclopentajcjpirazolyl, 5,6-dihydro-4 / 7pyrrolo [1,2-o] pyrazolyl, 6 , 7-dihydro-5/7-pyrrolo [1,2-o] [1,2,4] triazole, 5,6,7,8-tetrahydro [1,2,4] tr¡ azolo [1,5-a] pyridinyl, 4,5,6,7-tetrahydropyrazolo [1,5-a] pyrinyl, 4,5,6,7 tetrahydro-1/7-indazolyl and 4,5,6, 7-tetrahydro-2/7-indazolyl. The heteroaryl may optionally be substituted, as appropriate, with 1 to 5 suitable substituents, as defined herein, such as fluoro, chloro, deutero, cyano, trifluoromethyl, (C_rC₆) alkoxy, (C₆-Cio) aryloxy, trifluoromethoxy, difluoromethoxy or (CrC₆)I rent.

Examples of heteroaryls and heterocycloalkyls single ring include furanyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, sopirrolilo, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl , oxatiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, sothiazolidinyl, thiaoxadiazolyl, oxathiazolyl, oxadiazolyl (which includes oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl or 1,3,4-oxadiazolyl), pyranyl (which includes 1,2-pyranyl or 1,4-pyranyl ), dihydropyranyl, pyridinyl, piperidinyl, diazinyl (which includes pyridazinyl, pyrimidinyl, piperazinyl, triazinyl (which includes s-triazinyl, as-triazinyl and v-triazinyl), oxazinyl (which includes 2 / 7-1,2-oxazinyl / 7-1,3-oxazinyl or 2 / 7-1,4-oxazinyl), isoxazinyl (which includes o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (which includes 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (which includes 2 / 7-1,2,4-oxadiazinyl or 2 / 7-1,2,5 -oxadiazinyl) and morpholinyl.

The term "heteroaryl" also includes fused ring systems having one or two rings, where the rings can be fused, where fused is as defined above. It should be borne in mind that if a carbocyclic or heterocyclic portion can be linked or otherwise bound to a particular substrate by various ring atoms without indicating a specific binding point, then all possible points are anticipated, either by an atom of carbon or, for example, a trivalent nitrogen atom. For example, the term "pyridyl" means 2-, 3- or 4-pyridyl, the term "thienyl" means 2- or 3-thienyl, and so on.

In some cases, the amount of atoms in a cyclic substituent that contains one or more heteroatoms (ie, heteroaryl or heterocycloalkyl) is indicated by the prefix "x and members, where 'x' is the minimum amount, e 'and' ss the

-12 maximum amount of atoms that form the cyclic portion of the substituent. Accordingly, for example, 5-6 membered heteroaryl refers to a heteroaryl containing 5 to 6 atoms, which includes one or more heteroatoms, in the cyclic portion of the heteroaryl. The heteroatoms for this invention are selected from nitrogen, oxygen and sulfur.

The compounds of the present invention may contain basic nitrogen atoms (for example, alkylamines or heterocycles, such as pyridine, etc.) that can be converted to N-oxides by treatment with an oxidizing agent (eg, MCPBA and / or hydrogen peroxides) to obtain other compounds of the present invention. Therefore, all nitrogen-containing compounds that can be converted into N-oxid derivatives (N -► O or -N + -O-) form part of the invention.

A person of the medium level trade will understand that metabolites can be formed as part of the natural biochemical process of degradation and elimination of compounds. For example, some compounds of the invention can naturally form an N-oxide, as indicated below in the compound of the Formula lf 'or in other areas of the compound of the Formula la. Metabolites, such as these or others, that are part of the natural biochemical process are within the scope of the invention.

<img file="CU20160149A7_D0002.tif" />

Ilf Hf

If the substituents are described as having "independently more than one variable, each instance of a substituent is independently selected from each other from the list of available variables. Therefore, each substituent may be identical or different from the other substituents.

The terms "patient" or subject refer to warm-blooded animals, such as guinea pigs, mice, rats, gerbils, cats, rabbits, dogs, cattle, goats, sheep, horses, monkeys, chimpanzees and humans;

-13 The term "pharmaceutically acceptable" refers to the substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising a formulation, and / or with the mammal that is treated with them.

The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, improves or eliminates one or more symptoms of the disease, condition or particular disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition or disorder described herein;

As used herein, the term "treating", unless otherwise indicated, means reversing, alleviating, inhibiting progression, slowing progression, slowing onset or avoiding the condition or disorder referred to in said term, or one or more symptoms of the disorder or condition. As used herein, the term "treatment", unless otherwise indicated, refers to the act of treating, as just defined treating. The term "treat" also includes treatment with adjuvant or neoadjuvant of a subject. For the avoidance of doubt, "treatment" includes any curative, palliative and prophylactic treatment, and the administration of a medication for use in such treatment.

As used herein, the terms "Formula I", "Formula la", Formula lla-llg "," Formula III "and" Formula Illa "may hereinafter be referred to as" compounds of the invention "" the present invention and, taken together, the "compound of Formula I." Accordingly, the expression "compound of Formula I includes the compounds of Formulas la, lla-llg, III and Illa. Such terms also include all forms of the compound of Formula I, including hydrates, solvates, isomers, crystalline and non-crystalline forms, isomorphs, polymorphs, tautomers and metabolites thereof. For example, the compounds of the invention or the pharmaceutically acceptable salts thereof may exist in both non-solvated and solvated form. When the solvent or water are fixed closely, the complex has a well-defined stoichiometry independent of moisture. However, when the solvent or water are weakly fixed, as in solvates of channels and hygroscopic compounds, the water / solvent content will depend on the humidity and drying conditions. In those cases, the usual is the absence of stoichiometry.

-14 The compounds of the invention may have asymmetric carbon atoms. The carbon-carbon bonds of the compounds of the invention can be represented using a continuous line (-), a continuous wedge (—— «) or a dotted wedge (.............. The use of a continuous line to represent bonds with asymmetric carbon atoms is intended to indicate that all possible stereoisomers (eg, specific enantiomers, racemic mixtures, etc.) are included in that carbon atom. The use of a continuous or dotted wedge to represent bonds with asymmetric carbon atoms is intended to indicate that only the stereoisomer shown is included. It is possible that the compounds of Formula I contain more than one asymmetric carbon atom. In these compounds, the use of a continuous line to represent bonds with asymmetric carbon atoms is intended to indicate that all possible stereoisomers are included. For example, unless otherwise indicated, it is intended that the compounds of Formula I may exist as enantiomers and diastereomers or as racemates and mixtures thereof. The use of a continuous line to represent bonds with one or more asymmetric carbon atoms in a compound of Formula I and the use of a continuous or dotted wedge to represent bonds with other asymmetric carbon atoms in the same compound is intended to indicate the presence of a mixture of diastereomers.

The stereoisomers of Formula I include cis and trans isomers, optical isomers, such as the R and S enantiomers, diastereomers, geometric isomers, rotation isomers, conformational and tautomeric isomers of the compounds of the invention, including compounds that show more of a type of isomerism; and mixtures of these (such as racemates and pairs of diastomers). Also included are acidic or basic addition salts, wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DLtartrate or DL-arginine.

The compounds of the invention can exhibit the phenomenon of tautomerism. For example, the compound of Example 173 may exist in several tautomeric forms, including the pyrrolidine-2-one form, Example 173a, and the 5-hydroxy-3,4-dihydro-2H-pyrrole form, Example 173b. All tautomeric forms are within the scope of the compounds of Formula I and the scope of the invention. A person of the middle level trade will understand and recognize that

-15 Many of the examples described herein may exhibit tautomerism and are within the scope of the compound of Formulas I, la, lla-llg. III and Illa. Tautomers exist as mixtures of a tautomeric assembly in solution. Generally, in solid form, a tautomer predominates. While a tautomer can be described, the present invention includes all tautomers of the compounds of the

<td colspan="3">invention and its salts. Examples of tautomers are described by the</td>

<td>Examples 173a and 173b.</td><td>»B</td><td>HO k</td>

<td></td><td></td><td>.j</td>

<td> °\</td><td></td><td>Ox / Y ^ L</td>

<td>H₂N. /</td><td></td><td>H₂ N</td>

<td> 0</td><td></td><td> 0</td>

<td></td><td>Example 173a</td><td>Example 173b</td>

When a racemate crystallizes, it is possible that two different types of crystals are produced. The first type is the racemic compound (true racemate) mentioned above, where a homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic or conglomerate mixture, where two crystal forms are produced in equimolar amounts, each of which comprises a simple enantiomer.

The compounds of the present invention can be used in the form of salts derived from organic or inorganic acids. Depending on the particular compound, a salt of the compound may be beneficial due to one or more of the physical properties of the salt, such as a better pharmaceutical stability at different temperatures and humidity, or a desirable water or oil solubility. In some cases, a salt of a compound can also be used as an aid to the isolation, purification and / or resolution of the compound.

When a salt is used for administration to a patient (as opposed, for example, for use in an in vitro context), preferably, the salt is a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to a salt prepared by combining a compound of Formula I with an acid whose anion, or a base whose cation, in

-16general, they are considered suitable for human consumption. Pharmaceutically acceptable salts are particularly useful as products of the methods of the present invention, due to a higher aqueous solubility in relation to the compound of origin. With respect to their use in medicine, the salts of the compounds of the present invention are non-toxic "pharmaceutically acceptable salts." The salts included in the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention which, in general, are prepared by reacting the free base with a suitable organic or inorganic acid.

Suitable pharmaceutically acceptable acid addition salts of the compounds of the present invention, when possible, include those derived from inorganic acids, such as hydrochloric acid, hydrobromic, hydrofluoric, boric, fluoroboric, phosphoric, metaphosphoric, nitric, carbonic, sulfonic and sulfuric, and organic acids, such as acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isotionic, lactic, lactobionic, maleic, malic, methanesulfonic, trifluoromethanesulfonic, succinic, toluenesulfonic, tartaric and trifluoroacetic. Generally, suitable organic acids include, for example, the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic acid classes.

Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranyllate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, alginate, β-hydroxybutyrate, galactarate, galacturonate, adipate, alginate, butyrate, canforate, camphorsulfonate, cyclopentanepropionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, heptanoate, hexanoate, nicotinate,

2-naphthanesulfonate, oxalate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, thiocyanate and undecanoate.

Also, when the compounds of the invention have an acidic portion, the pharmaceutically acceptable salts thereof include alkali metal salts, for example, sodium or potassium salts; alkaline earth metal salts,

-17 for example, calcium or magnesium salts; and salts formed with suitable organic ligands, for example, quaternary ammonium salts. In another embodiment, the basic salts are formed from bases that form non-toxic salts, including aluminum, arginine, benzathine, choline, diethylamine, diolamine, glycine, lysine, meglumine, olamine, tromethamine and zinc salts.

Organic salts may be formed from secondary, tertiary or quaternary amine salts, such as tromethamine, diethylamine, Λ /, Λ / '- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (/ V-methylglucamine) and procaine. Groups containing basic nitrogen can be quaternized with agents, such as alkyl halides (C_rC₆) lower (for example, chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (i.e., chlorides, bromides and decyl, lauryl, myristyl and stearyl iodides), arylalkyl halides (eg, benzyl and phenethyl bromides), and others.

In one embodiment, hemispheres of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.

The present invention also includes so-called "prodrugs" of the compound of the invention. Therefore, certain derivatives of the compound of the invention that may have little or no pharmacological activity, can be converted, when administered in the body, into the compound of the invention that has the desired activity, for example, by hydrolytic cleavage. These derivatives are called prodrugs. [More information on the use of prodrugs can be obtained in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series ((T. Higuchi and V. Stella) and' Bioreversible Carriers in Drug Design ', Pergamon Press, 1987 (ed. EB Roche, American Pharmaceutical Association). Prodrugs according to the invention can be obtained, for example, by replacing the suitable functionalities present in the compounds of any of Formula I with certain portions known to those skilled in the art as 'pro-portions', as described, by example, in Design of Prodrugs' by H. Bundgaard (Elsevier, 1985).

The present invention also includes isotopically labeled compounds, which are identical to those listed in Formula I, except that one or more atoms are replaced by an atom that has an atomic mass or mass number

-18 different from the atomic mass or mass number that is usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine and chlorine, such as²H ³H ¹³C, ¹¹C, ¹⁴C, ¹⁵N, ¹⁸OR, ¹⁷OR, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. The compounds of the present invention, the prodrugs thereof and the pharmaceutically acceptable salts of said compounds or prodrugs, which contain the aforementioned isotopes and / or other isotopes of other atoms, are within the scope of this invention. . Certain isotopically labeled compounds of the present invention, for example those in which radioactive isotopes are incorporated, such as³H and ¹⁴C, are useful in distribution assays in substrate tissue and / or drug. Titrated isotopes, that is,³H, and carbon-14, that is, ¹⁴C, are particularly preferred for their simple preparation and detectability. In addition, replacement with heavier isotopes, such as deuterium, that is,²H, may provide certain therapeutic advantages that are the result of greater metabolic stability, for example, longer half-life in vivo or less dosage requirements and, therefore, may be preferable in some circumstances. The compounds of the invention according to the claims can specifically define substitution with deutero or deuterium. The absence of the terms deuteron, deuteron or deuterium, which are used interchangeably, in a substitution group should not pretend to exclude deutero.

Therefore, the isotopically labeled compounds of the Formula I of the present invention and the prodrugs thereof, in general, can be prepared by performing the procedures described in the Schemes and / or in the Examples and the Preparations described below, replacing an easily available isotopically labeled reagent with an isotopically unlabelled reagent.

Compounds of the invention

<img file="CU20160149A7_D0003.tif" />

the where

X and X 'are, each independently, CR⁸, No N⁺-OR'; And it is, independently, Ν, -N⁺-O'o CR⁸; provided that at least one of X, X 'or Y is not N or -N⁺-O ~ and that no more than one of X, X 'or Y is -N⁺-OR; or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

In one aspect, the invention provides the compounds of Formula la, wherein X is Ν, X 'is CR⁸, and Y is CR⁸; X is Ν, X 'is N, and Y is CR⁸ ; X is Ν, X 'is CR⁸, and Y is Ν; X is CR⁸, X 'and Y are Ν; X and X 'are CR⁸, and Y is Ν; X is CR⁸, and Y is CR⁸', and X' is Ν; X and X 'are CR⁸, and Y is CR⁸'; or a pharmaceutically acceptable salt of the compound or a tautomer of the salt. In another aspect, R⁶ is -C (O) NHR⁷, -CO₂R⁷ or cyano; and R⁷ it is hydrogen; or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

The invention also provides a compound of the Formulas lia, llb, lie, lid, lie, Ufo llg,

<img file="CU20160149A7_D0004.tif" />

where R¹ is (f-Cealkyl; C2-C6alkenyl; C2-C6alkyl; - (CR^3rdR^3b) m (cycloaquid of 3 to 7 members); or - (CR^3rdR^3b) m- (3 to 7-membered heterocycloalkyl) having 1 to 3 heteroatoms; wherein alkyl, alkenyl, alkynyl, cycloalkyl or heterocycloalkyl are optionally substituted with 1 to 5 halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11b, cyano, CrCealkyl, C3-C₆cycloalkyl or -CrCealkoxy;

R² is - (CR^3rdR^3b) m- (3 to 7 membered cycloalkyl), wherein the cycloalkyl is optionally substituted with 1 to 4 R⁴; - (CR^3rdR^3b) m- (3 to 7-membered heterocycloalkyl) having 1 to 3 heteroatoms, wherein the heterocycloalkyl is optionally substituted on a carbon atom with 1 to 5 R⁴, and where, if the heteroatom is Ν, N is optionally substituted with R⁴; or R² it's Ci-C₆alkyl, wherein the alkyl is optionally substituted with NH₂, cyano or halogen

-21R^3rd and R^3b they are, each independently, hydrogen or CrC₃I rent;

R⁴ it is, for each case independently and optionally, halogen, cyano, CrO6alkyl, C2-C6alkenyl, oxo, -OR⁵, -MR⁵, -S (O) R⁹, -S (O) 2R⁹, C (O) R¹⁰, - (CR^3rdR^3b) n- (cycloalkyl of 3 to 7 members) or - (CR^3rdR^3b) n (4 to 7 membered heterocycloalkyl), wherein the alkyl, cycloaiquyl or heterocycloalkyl are each substituted independently and optionally with 1 to 5 deuterium, halogen, -OR⁵, -MR⁵, -NR^11thR^11b, cyano, Ci-C6alkyl, C3-C6cycloalkyl, CrC6aicox¡ or NR^11thR^11b; or two R⁴, together with the respective carbons to which they are attached, form a 3-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11b, cyano or CrC6alkyl or CrC₆alkoxy, wherein the alkyl or alkoxy is optionally substituted with halogen, deuterium, -OR⁵, -NR^11thR^11b or cyano; and where, if a heteroatom in that heterocycloalkyl is Ν, N is optionally substituted with R⁴;

R⁴'is independently CrCealkyl, C2-C6alkenyl, -S (O) R⁹, S (O) 2R⁹, -C (O) R¹⁰, C (O) (CH2) tCN; wherein alkyl is optionally substituted with NH2, cyano or halogen - (CR^3rdR^3b) n- (cycloalkyl of 3 to 7 members) or (CR^3rdR^3b) n (4-10 membered heterocycloaiquyl), wherein the alkyl, alkenyl, cycloalkyl or heterocycloalkyl are each substituted independently and optionally with 1 to 5 deuterium, halogen, OH, cyano or CrC6alkoxy; or R⁴ and R⁴ together with the respective atoms to which they are attached, they form a 3-6 membered cycloalkyl or a 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11b, cyano, CrCealkyl or CrC6alkoxy, wherein alkyl or alkoxy is optionally substituted with halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11b or cyano;

R⁵ is hydrogen or CrC₆alkyl, wherein the alkyl is optionally substituted with halogen;

R⁶ is -C (O) NHR⁷ or cyano;

R⁷ is hydrogen or CrC₆ I rent;

R⁸ is, independently, hydrogen, halogen, cyano, -NR^11thR^11b, Cr C6alkyl, 5-6 membered heteroaryl or 5-6 membered aryl, wherein the alkyl or heteroaryl or aryl is optionally substituted with 1 to 3 halogen, NR^11thR^11b, CrC3 alkyl or oxo;

-22R⁸'is hydrogen, deuterium, halogen, cyano, -OR⁵ or NR^11thNR^11b;

R⁹ is - (CR^3rdR^3b) p- (CrC3alkyl), - (CR^3rdR^3b) p- (cycloalkyl of 4 to 6 members), - (CR^3rdR^3b) p- (4- to 6-membered heterocycloalquiium) or - (CR^3rdR^3b) p- (C₅C₉aryl), wherein the alkyl, cycloalkyl, heterocycloalkyl or aryl are each optionally substituted with fiuoro or Ci-C₃rent it;

R¹⁰ it's Ci-C₆alkyl, wherein alkyl is optionally substituted with fiuoro or cyano;

R^11th and R^11b they are, each independently, hydrogen or CrCgalkyl, wherein alkyl is optionally substituted with OH;

m is, independently, 0.1 or 2; n is, independently, 0 or 1; p is independently 0 or 1; and t is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

In one aspect of the Invention, R¹ it is C1-C4alkyl; C2-C4alquen¡lo; C2C4alkium; - (CR^3rdR^3b) m- (3 to 6 members); o ~ (CR^3rdR^3b) m (3 to 5 membered heterocycloalqullo) having 1 to 3 heteroatoms; wherein the alkyl, alkenium, alkynyl, cycloalkyl or heterocycloalkyl optionally is substituted with 1 to 3 halogen, deuterium, -OR⁵, -MR⁵, -NR^11thR^11b, cyano, Cr C_salkyl, C₃-C₆cycloalkyl or CrCsalkoxy; R^3rd and R^3b they are, each independently, hydrogen or C_rC₃I rent; R^s is -C (O) NHR⁷ or cyano; R⁷ it is hydrogen; and m is independently 0 or 1.

In another aspect, the invention provides compounds wherein R¹ it is fluoromethyl; difluoromethyl; trlfluoromethyl; methyl, ethyl, propyl or isopropyium, each optionally substituted with 1 to 3 fiuoro or deuterium; alloy, propargyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, oxetane or tetrahydrofuran, each of which is optionally substituted with fiuoro or Ci-C₃ I rent.

In another aspect, R² is selected from pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, plperidin-2-οηιΊο, octahydro-1/7-pyrrole [3,4-c] pyrinyl, oxazolldlnyl, oxazolidine-2-one! , 1,3-oxazlnan-2-onyl, imidazolidinyl, imldazolldln-2-onyl, morpholinyl, morpholin-3-onyl, thiazyl, isothiazyl, isothiazolidln-1,1-dioxidyl, 1,2-thiazinan

1,1-dioxidyl, hexahydrocloclopenta / to / pyrrole-2 (1 H) -onyl,

-23octahydroci clopentajc] pyrro I i o, azetidi ni lo, hexahydro-1 W-indol-2 (3H) -onyl, octahydro-IH-isoindolyl, azepanyl, tetrahydrofuranyl, 1,3-dioxolanyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-azepanyl, 1,4-oxazepanyl, tetrahydro-2H-pyranyl, 6,7-dihydro-5H-pyrrolo [1,2-a] imidazolyl, cyclohex-2-enyl or

1,2,3,4-tetrahydroisoquinolinyl; wherein alkyl, cycloalkyl or heterocycloalkyl are optionally substituted with 1 to 4 R⁴.

In another aspect, the cycloalkyl and the heterocycloalkyl of R² are optionally substituted with 1 to 4 R⁴; or two R⁴, together with the respective carbons to which they are attached, form a 3-6 membered cycloalkyl or 4-6 membered heterocycloalkyl, wherein the cycloalkyl or heterocycloalkyl is optionally substituted with 1 to 3 F, Cl, OH, cyano, Ci -C3alkyl (optionally substituted with OH, F or Ci), CrC3fluoroalkyl or CrC6alkoxy; R^that it is, independently, hydrogen, deuterium or Ci-C3alkyl, wherein the alkyl is optionally substituted with halogen; R^3rd and R^3b they are, for each case independently, hydrogen or Cr C3 alkyl; R⁴ it is, for each case independently and optionally, halogen; CrCsalquilo; C2-C₄alkenyl; oxo; -OR⁵; -C (O) R¹⁰; - (CR^3rdR^3b) n (cycloalkyl of 3 to 5 members); or - (CR^3rdR^3b) n- (4 to 7-membered heterocycloalkyl), wherein the alkyl, cycloalkyl or heterocycloalkyl are each independently and optionally substituted with 1 to 5 deuterium, halogen, OH, cyano, CrCsalkoxy or -NR^11thR^11b; or two R⁴, together with the respective carbons to which they are attached, form a cyclopropyl, cyclobutyl or cyclopentyl, wherein the cyclopropyl, cyclobutyl or cyclopentyl are optionally substituted with 1 to 3 halogen, OH, methyl, ethyl, propyl, CrC3fluoroalkyl, CrCshidroxyalkyl, methoxy or ethoxy; or two R⁴, together with the respective carbons to which they are attached, form a 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 3 fluoro, CrC₃alkyl or Ci-CYluoroalkyl; R⁵ it is hydrogen, methyl or ethyl; R⁹ it is phenyl; R¹⁰ it's CrC₆alkyl, wherein the alkyl is optionally substituted with fluoro or cyano; and R^11th and R^11b they are, each independently, H or CrCsalquilo; or a pharmaceutically acceptable salt thereof or a tautomer of the compound or salt.

In another aspect, R⁴ is selected from F, Cl, OH; Ch-Csalkyl optionally substituted with 1 to 5 deuterium, Cl, F, OH, Ci-Csalquilo, CrCsalcoxi; or two R⁴, together with the respective carbons to which they are attached, form a cyclopropyl, a

-24 cyclobutyl or a cyclopentyl, wherein the cyclopropyl, cyclobutyl or cyclopentyl are optionally substituted with 1 to 3 Cl, F, OH, methyl, ethyl, propyl, C_rC₃fluoroalkyl, CpCshydroxyalkyl, methoxy or ethoxy; or two R⁴, together with the respective carbons to which they are attached, form a 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 3 fluoro, Ci-C₃alkyl, Ci-C₃fluoroalkyl, -C (O) (CH₂)_tCN; or a pharmaceutically acceptable salt thereof or a tautomer of the compound or salt.

In another embodiment, the invention relates to a compound of Formula III

<img file="CU20160149A7_D0005.tif" />

III where

X and X 'are, each independently, CR⁸ or N; And it is independently N or CR⁸; provided that at least one of X, X 'or Y is not N;

R¹ is CrCealkyl or C_rC₆cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted with deuterium, halogen, OH, cyano, C_rC₃Rent it, C₃C₆cycloalkullo, C ^ Cgalcoxy or CrCealkylthiolyl;

R^3rd and R^3b they are, each independently, hydrogen or C_rC₃I rent;

R⁴ is, for each case (1, 2, 3, 4 or 5) independently and optionally, halogen, CrCealkyl, C2-C6alkene -OR⁵, - (CR^3rdR^3b) n- (cycloalkyl of 3 to 6 members) or - (CR^3rdR^3b)_n- (4-6-membered heterocycloalkyl), wherein the alkyl, cycloalkyl or heterocycloalkyl are each substituted independently and optionally with 1 to 5 deuterium, halogen, OH, CN, -C (O) (CH₂)_tCN or -CrCealkoxy; -NR^11thR^11b; two R⁴, together with the respective carbons to which they are attached, form a cyclopropyl, a cyclobutyl or a cyclopentyl, in which the cicioproprio, cyclobutyl or cyclopentyl are substituted

-25 optionally with 1 to 3 F, Cl, OH, methyl, ethyl, propyl, CrCsfluoroalkyl, C- | -C₃cl? fluoroalkyl, C_rC₃trifluoroalkyl, Ci-Cshidroxyalkyl, methoxy or ethoxy;

R⁵ it is hydrogen or Ci-Cealkyl, wherein the alkyl is optionally substituted with fluoro;

R⁸ is, independently, hydrogen, halogen, cyano, -NR^11thR^11b, Cr C6 alkyl, heteroaryl or aryl of 5 to 6 members, wherein the alkyl or heteroaryl or aryl is optionally substituted with 1, 2 or 3 halogen, -NR^11thR^11b, CrC₃ alkyl or oxo;

R⁸'is hydrogen, deuterium, halogen or cyano;

R¹⁰ it's Ci-C₆alkyl, wherein alkyl is optionally substituted with fluoro or cyano;

pna and pub _gon, _cgcj_{to aQ} ¡_ncj_andp_ind¡_int_ernente, hydrogen or CrCgalkyl, wherein the alkyl is optionally substituted with OH;

n is, independently, 0 or 1; and t is 1, 2 or 3;

or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

In one aspect, the invention relates to compounds, wherein Y is Ν; X and X 'are CR⁸. In another aspect, X and X 'are each CR⁸, and Y is CR⁸ In another aspect, X and Y are N, and X 'is CR⁸. In another aspect, X is Ν, X 'is CR⁸, and Y is CR⁸.

In another aspect, R¹ it is CrCsalkyl, wherein the alkyl is optionally substituted with 1 to 3 deuterium, F, Cl or Ci-C3alkox¡; and R^3rd and R^3b they are, each independently, hydrogen or methyl. In another aspect, R⁴ it is, for each case independently and optionally, F; Cl; OH; or CrCsalkyl, optionally substituted with 1 to 5 deuterium, Cl, F, OH, CrC3alkyl or C- | -C₃alkoxy; or two R⁴together with the carbons to which they are attached, they form a cyclopropyl, cyclobutyl or cyclopentyl, wherein cyclopropyl, cyclobutyl or cyclopentyl are optionally substituted with 1 to 3 Cl, F, OH, methyl, ethyl, propyl, Ci-C3haloalkyl, C1-C3 dihaloalkyl, Cr C3trihaloalkyl, C-C3hydroxyalkyl, methoxy or ethoxy; or two R⁴, together with the carbons to which they are attached, form a 4- to 6-membered heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with 1 to 3 fluoro, CrCsalkyl, CrC3fluoroalkyl or -C (O) (CH₂)_tCN

-26 Still in another aspect, R¹ it is methyl, ethyl, propyl or isopropyl, where each of the portions R¹ they are optionally substituted with deuterium, fluoro or methoxy; R⁴ is selected, independently and optionally, from fluoro, OH, methyl, ethyl, vinyl, propyl, wherein methyl, ethyl, vinyl or propyl are optionally substituted with 1, 2 or 3 fluoro, OH or methoxy; or two R⁴, together with the carbons to which they are attached, form a cyclopropyl, cyclobutyl or cyclopentyl, wherein cyclopropyl, cyclobutyl or cyclopentyl are optionally substituted with 1 to 3 Cl, F, OH, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxymethyl, propyl, CpCshaloalkyl, CrCsdihaloalkyl, C_rC3trihaloalkyl, Ci-C₃hydroxyalkyl, methoxy or ethoxy; and R⁸ it is, independently, hydrogen, halogen or C ^ Csalkyl, wherein the alkyl is optionally substituted with fluoro.

In another embodiment, the invention relates to a compound of the Formula Illa,

<img file="CU20160149A7_D0006.tif" />

where

X and X 'are, each independently, CR⁸ or N; And it is independently N or CR⁸; provided that at least one of X, X 'or Y is not N;

R¹ is C_rC₆alkyl, wherein the alkyl is optionally substituted with deuterium, halogen, OH, C ^ Csalkyl, C₃-C₆cycloalkyl or Ch-Cgalkoxy;

R^3rd and R^3b they are, each independently, hydrogen or Ch-Csalquilo;

R^4th and R^4b they are, each independently, hydrogen, deuterium, fluoro,

OH -OR⁵, methyl, ethyl, vinyl, cyclopropyl or propyl, optionally substituted with 1 to 5 deuterium, fluoro, methoxy or OH;

R^4c and R^4d they are, independently and optionally, halogen, OH, deuterium, CrC6alkyl, C2-C6alkenyl, -OR⁵, - (CR^3rdR^3b) n (cycloalkyl of 3 to 6 members) or - (CR^3rdR^3b) n- (heterocycloalkyl of 4 to 6-27 members), wherein the alkyl, cycloalkyl and heterocycloalkyl are substituted, each independently and optionally, with 1 to 5 deuterium, halogen, OH, cyano or CrCealkoxy; NH2; or R^4c and R^4d, together with the carbons to which they are attached, form a 4-7 membered heterocycloalkyl or a 3-7 membered cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 3 fluoro, CrC₃alkyl or CrCsfluoroalkyl; or

R^4th and R^4btogether with the carbon to which they are attached, they form a 4- to 7-membered heterocycloalkyl or a 3- to 7-membered cycloalkyl, wherein the heterocycloalkyl or cycloalkyl is optionally substituted with 1 to 3 fluoro, C_rC₃alqullo or CrC₃fiuoroalkyl;

R⁵ is hydrogen or Ci-C₆alkyl, wherein the alkyl is optionally substituted with fluoro;

R⁸ it is hydrogen, halogen or Ch-Csalkyl, wherein the alkyl is optionally substituted with halogen;

R® is hydrogen, deuterium, halogen or cyano; and n is independently 0 or 1;

or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

In one aspect, the invention provides R⁸it is hydrogen, methyl or fluoro; R¹ it is methyl, ethyl, isopropyl or propyl, opclonally substituted with deuterium; R^4th it is hydrogen; methyl, ethyl or propyl, optionally substituted with deuterium, fluoro, methoxy; R^4b it is hydrogen or fluoro; R^4c it is hydrogen or OH; R^4d it is hydrogen, fluoro, methoxy or OH; or methyl, optionally substituted with 1, 2 or 3 fluoro; or ethyl, optionally substituted with 1, 2 or 3 fluoro; or R^4c and R^4d or, alternatively, R^4th and R^4c, together with the carbons to which they are attached, form a cyclopropyl, optionally substituted with 1 to 3 fluoro, Cf-Csalqullo or C_rC₃fluoroalkyl; or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

In another embodiment, the invention relates to the compounds described in Tables 1 or 3; or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

In another embodiment, the invention relates to the Intermediate compounds described in Table 2; or a pharmaceutically acceptable salt of the compound or a tautomer of the compound or salt.

-28 In another embodiment, the invention relates to a process and a synthesis preparation of the intermediate compounds described in Table 2, as detailed in the schemes and the preparation section described herein. In another aspect, the invention relates to a process of synthesis and preparation of the compounds of Tables 1 or 3, as detailed in the schemes and the section of preparations described herein.

IRAK4 Indications

The compounds of the invention are also useful in the treatment and / or prevention of a disease or condition mediated by or associated with an IRAK enzyme; The method comprises administering to an individual in need an effective amount of a compound of the invention.

The disease can be, among others, one of the following classes: autoimmune diseases, inflammatory diseases, allergic diseases, metabolic diseases, infectious diseases, trauma or diseases due to tissue lesions, fibrotic diseases, genetic diseases, diseases driven by the overactivity of the IL1 pathways, cardiovascular diseases, vascular diseases, heart diseases, neurological diseases , neurodegenerative diseases, respiratory diseases, lung diseases, airway diseases, kidney diseases, dermatological and / or skin diseases, liver diseases, gastrointestinal diseases, oral diseases, sensory and pain diseases, hematopoietic diseases, arthropathies, muscle diseases, bone diseases and ophthalmic and / or eye diseases .

Specific autoimmune diseases include, among others: rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, systemic lupus erythematosus (and resulting complications), Sjógren's syndrome, multiple sclerosis, asthma, glomerular nephritis, irritable bowel syndrome, inflammatory bowel disease, Crohn's disease, ankylosing spondylitis, Behget's disease , lupus nephritis, scleroderma, systemic scleroderma, juvenile or type 1 diabetes, alopecia universalis, acute disseminated encephalomyelitis, Addison's disease, antiphospholipid antibody syndrome, atrophic gastritis of pernicious anemia, autoimmune alopecia, autoimmune hemolytic anemia, autoimmune hepatitis,

-29 autoimmune encephalomyelitis, autoimmune thrombocytopenia, bullous pemphigoid, Chagas disease, celiac disease, chronic hepatitis, Cogan syndrome, dermatomyositis, endometriosis, Goodpasture syndrome, Graves disease, Guillain-Barré syndrome, Hashimoto's disease (or Hashimoto's thyroiditis) , hemolytic anemia, suppurative hydradentitis, idiopathic thrombocytopenic purpura, interstitial cystitis, membranous glomerulopathy, morphea, myasthenia gravis, narcolepsy, pemphigus, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, Reiter's syndrome, schizophrenia, sympathetic ophthalmia, systemic sclerosis, temporal arteritis, thyroiditis, vasculitis, vitiligium, vulvodynia, Wegner granulomatosis, palmoplantar keratoderma, idiopathic systemic arthritis1 ) or an indication listed in a separate category here.

Specific inflammatory diseases include, among others: chronic obstructive pulmonary diseases, hyperreactivity of the airways, cystic fibrosis, acute respiratory distress syndrome, sinusitis, rhinitis, gingivitis, atherosclerosis, chronic prostatitis, glomerular nephritis, ulcerative colitis, uveitis, periodontal disease or an indication listed in a separate category here.

Specific pain conditions include, among others: inflammatory pain, surgical pain, visceral pain, odontalgia, premenstrual pain, central pain, pain caused by burns, migraines or headache in outbreaks, nerve injury, interstitial cystitis, cancer pain, viral infection, parasitic or bacterial, post-traumatic injury, pain associated with irritable bowel syndrome, gout, pain associated with any other indication listed within the present specification or an indication listed in a separate category here.

Pulmonary, respiratory and airway conditions include, among others: asthma (which may include chronic, late, bronchial, allergic, intrinsic, extrinsic or dust asthma), chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, arterial pulmonary hypertension, cystic fibrosis, interstitial lung disease, acute lung injury, sarcoidosis, allergic rhinitis , chronic cough, bronchitis, recurrent airway obstruction, emphysema or bronchospasm, or an indication listed in a separate disease category here.

-30 Specific gastrointestinal (Gl) disorders include, but are not limited to: irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, IBS with a predominance of diarrhea, pain associated with distension Gl, ulcerative colitis, Crohn's disease, irritable bowel syndrome, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis or an indication listed in a separate disease category here.

Specific allergic diseases include, but are not limited to: anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, allergic reactions to: food, drugs, insect bites, pollen; or an indication listed in a separate disease category herein.

Specific infectious diseases include, among others: sepsis, septic shock, viral diseases, malaria, Lyme disease, eye infections, conjunctivitis, Whipple's disease or an indication listed in a separate disease category here.

Injuries and conditions from specific tissue injuries include, but are not limited to; renal glomerular damage, reperfusion injury (for example cardiac, renal, pulmonary), spinal cord injury, tissue scars, tissue adhesion, tissue scarring, transplant rejection (e.g., heart, lung, bone marrow, cartilage, cornea, kidney, limb, liver, muscle, myoblast, pancreas, pancreatic islet, skin, nerve, small intestine, trachea), hypersensitivities or an indication listed in a separate disease category here.

Specific fibrotic diseases include, among others: idiopathic pulmonary fibrosis, liver fibrosis, renal fibrosis or an indication listed in a separate disease category here.

The specific diseases considered are driven by the overactivity of the IL1 pathways include, among others: The periodic syndromes associated with cryopyrine, myositis and indications included in the following review article: CA Dinarello, A. Simón and JWM van der Meer, Treating infiammation by blocking interleukin-1 in a broad spectrum of diseases, Nat Rev Drug Discov, 2012, 11 (8), 633-652, http://dx.doi.org/10.1038/nrd3800 and additional information contained therein, or an indication listed in a separate disease category herein.

-31 Specific ophthalmic / eye diseases include, among others: uveitis, age-related macular degeneration, diabetic macular edema, keratoconjunctivitis, uveitis associated with Behget's disease, spring conjunctivitis, keratitis, contact lens induced uveitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, ocular pemphigus of Mooren, scleritis, Graves ophthalmopathy, Vogt-Koyanagi-Harada syndrome, dry keratoconjunctivitis, phlictenulosis, iridocyclitis, sympathetic ophthalmia, allergic conjunctivitis, ocular neovascularization, dry eye syndrome or an indication listed in a separate disease category here.

Specific joint, muscle and bone disorders include, among others: osteoarthritis, osteoporosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, erosive osteoarthritis of the hand, arthrofibrosis / traumatic knee injury, rupture of the anterior cruciate ligaments of the knee, recurrent polychondritis, recurrent multifocal osteomyelitis, Majeed syndrome, ankylosing spondylitis, ankylosing spondylitis of the lumbar spine, antisintetase syndrome, idiopathic inflammatory myopathies, articular chondrocalcinosis, Systemic onset juvenile idiopathic arthritis (SJIA), gout and pyrophosphate crystal arthritis or an indication listed in a separate disease category here.

Specific dermatological / skin diseases include, among others: psoriasis, atopic dermatitis, cutaneous lupus, acne, dermatomyositis, eczema, pruritus, scieroderma, Sweet syndrome / neutrophilic dermatosis, neutrophilic panniculitis, acrodermatitis (pustular psoriasis form) or a Indication listed in a separate disease category here.

Specific kidney diseases include, among others: acute renal injury (AKI) (AKI by sepsis, AKI by coronary bypass graft, AKI by cardiac surgery, AKI by non-cardiac surgery, AKI by transplant surgery, AKI by cisplatin, AKI induced by contrast agents / imaging agents, glomerulonephritis, IgA nephropathy, semilunar GN, lupus nephritis, HIV-associated nephropathy, membranous nephropathy, C3 glomeruiopathy, dense deposits disease, ANCA vasculitis, diabetic nephropathy, hemolytic-uremic syndrome, Atypical hemotitic syndrome, nephrotic syndrome, nephrotic syndrome, hypertensive nephrosclerosis, ApoL1 nephropathy, focal segmental glomerulosclerosis, Alport syndrome, Fanconí syndrome, crystalline nephropathy, nephrolithiasis, nephrotic syndrome, rejection of

-32 renal transplantation, amyloidosis, glomerulonephritis in SJIA or an indication listed in a separate disease category in the present.

Specific genetic diseases include, but are not limited to: familial Mediterranean fever (FMF), CAPS (FCAS, Muckle-Wells syndrome, NOMID / CINCA), male infertility in CAPS, NLRP12 self-inflammatory syndrome or an indication listed in a separate disease category at the moment.

Specific hematopoietic diseases include, but are not limited to: hemolytic anemia or an indication listed in a separate disease category here.

Specific liver diseases include, but are not limited to: liver fibrosis, liver cirrhosis, non-alcoholic steatohepatitls (NASH) or an indication listed in a separate disease category here.

Specific oral diseases include, among others: gingivitis, periodontal disease or an indication listed in a separate disease category here.

Specific metabolic diseases include, but are not limited to: type 2 diabetes (and resulting complications), gout and hyperuricemia, metabolic syndrome, insulin resistance, obesity or an Indication listed in a separate disease category here.

The compounds of the present invention are also useful in the treatment of a proliferative disease selected from benign or malignant tumor, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovarian carcinoma, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glloblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, neck and head tumor, epidermal hlperprollferation, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, carcinoma Non-small cell lung, Hodgklns and non-Hodgklns Hnfomas, breast carcinoma, follicular carcinoma, nondifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, multiple myeloma of poor malignancy or hematological cancer (which

-33 includes leukemia, diffuse large B lymphocyte lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, prolymphocytic B lymphocytic leukemia, lymphoma lymphoplasmacytic, Waldenstrom macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, Intravascular large B lymphocyte lymphoma) or an indication listed in a separate disease category here.

Cardiovascular conditions include, but are not limited to, coronary heart disease, acute coronary syndrome, ischemic heart disease, primary or recurrent myocardial infarction, secondary myocardial infarction, myocardial infarction without ST-segment elevation or myocardial infarction with ST-segment elevation, sudden death ischemic, transient ischemic accident, peripheral occlusive arteriopathy, angina, atherosclerosis, hypertension, heart failure (such as congestive heart failure), diastolic dysfunction (such as left ventricular diastolic dysfunction, diastolic heart failure and decreased diastolic filling), systolic dysfunction (such as systolic heart failure with decreased ejected fraction), vasculitis, vasculitis ANCA, postmyocardial infarction, cardiac restructuring, atrial fibrillation, arrhythmia (ventricuiar), ischemia, hypertrophic cardiomyopathy, sudden cardiac death, myocardial and vascular fibrosis, decrease in arterial compliance, necrotic lesions of the myocardium, vascular lesions, left ventricular hypertrophy, decrease in the ejected fraction, cardiac lesions, vascular wall hypertrophy, endothelial thickening, fibrinoid necrosis of coronary arteries, adverse restructuring, stroke and the like, or an indication listed in a separate disease category presently. Also included are phlebotrombosis, deep fiebotrombosis, thrombophlebitis, arterial embolism, coronary thrombosis, cerebral thrombosis, cerebral embolism, renal embolism, pulmonary embolism and thrombosis, which are the result of (a) prosthetic valves or other implants, (b) permanent catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis. It should be noted that thrombosis includes occlusion (for example, after a bypass) and reocclusion (for example, during or after percutaneous transluminal coronary angiopiasty).

-34 Cardiovascular complications of type 2 diabetes are associated with inflammation; accordingly, the compounds of the present invention can be used to treat diabetes and diabetic complications, such as macrovascular disease, hyperglycemia, metabolic syndrome, glucose intolerance, hyperuricemia, glucosuria, cataracts, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy , obesity, dyslipidemia, hypertension, hyperinsulinemia and insulin resistance syndrome, or an indication listed in a separate disease category herein.

The connection between innate immunity and inflammation with the disease has been demonstrated in neuroinflammatory and neurodegenerative conditions. Therefore, the compounds of the present invention are indicated in particular for use in the treatment of neuroinflammatory and neurodegenerative conditions (ie, disorders or diseases) in mammals, including humans, such as multiple sclerosis, migraine; epilepsy; Alzheimer disease; Parkinson's disease; brain injury; apoplexy; cerebrovascular diseases (including cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage and cerebral hypoxia-ischemia); cognitive disorders (including amnesia, senile dementia, HIV-associated dementia, dementia associated with Alzheimer's disease, dementia associated with Huntington's disease, dementia of Lewy bodies, vascular dementia, drug-related dementia, delirium and cognitive deficiency mild); mental deficiency (which includes Down syndrome and fragile X chromosome syndrome); sleep disorders (including hypersomnia, circadian sleep rhythm disorders, insomnia, parasomnia and sleep deprivation) and psychiatric disorders, such as anxiety (which include acute stress disorders, generalized anxiety disorders, social anxiety disorders, disorders of distress, posttraumatic stress disorders and obsessive compulsive disorder); factitious disorders (including acute hallucinatory mania); impulse control disorders (including gambling and intermittent explosive disorder); mood disorders (including bipolar I disorder, bipolar II disorder, mania, mixed affective episode, major depression, chronic depression, seasonal depression, psychotic depression and postpartum depression); psychomotor disorder; psychotic disorders (including schizophrenia, schizoaffective disorder, schizophrenic disorder and delusional disorder); drug dependence (which includes drug addiction, alcoholism, addiction to

-35 amphetamines, cocainomania, smoking and withdrawal syndrome); eating disorders (including anorexia, bulimla, binge eating disorders, hyperphagia and pagofagla); and pediatric psychiatric disorders (including attention deficit disorder, attention deficit hyperactivity disorder, behavioral and autism disorders), myotrophic lateral sclerosis, chronic fatigue syndrome or an indication listed in a separate disease category here.

In general, a compound of the invention is administered in an amount effective to treat a condition as described herein. The compounds of the invention are administered by any suitable route in the form of a pharmaceutical composition adapted to said route and in an effective dose for the intended treatment. The therapeutically effective doses of the compounds necessary to treat the progression of the medical condition are readily determined by one skilled in the art using preclinical and clinical approaches known in the medical arts.

The compounds of the invention can be administered orally. Oral administration may include swallowing, so that the compound enters the gastrointestinal tract, or the administration may be buccal or sublingual, so that the compound enters the bloodstream directly from the mouth.

In another embodiment, the compounds of the invention can also be administered directly to the bloodstream, muscle or internal organ. Suitable means for parenteral administration include intravenous, intraarterial, intraperitonal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous administration. Suitable devices for parenteral administration include Needle injectors (including ml needles), Needleless injectors and infusion techniques.

In another embodiment, the compounds of the invention can also be administered topically to the skin or mucosa, that is, dermally or transdermally. In another embodiment, the compounds of the invention can also be administered intranasally or by inhalation. In another embodiment, the compounds of the invention can also be administered rectally or vaginally. In another embodiment, the compounds of the invention can also be administered directly to the eyes or ears.

The dosage regimen of the compounds and / or compositions containing the compounds is based on several factors, including type, age, weight,

-36 sex and the patient's medical condition; the severity of the condition; the route of administration; and the activity of the particular compound that is used. Therefore, the dosage regimen can vary widely. Dosage levels in the order of about 0.01 mg to about 100 mg per kilogram of body weight per day are useful for the treatment of the conditions indicated above. In one embodiment, the total daily dose of a compound of the invention (administered in a single dose or in divided doses) is generally from about 0.01 to about 100 mg / kg. In another embodiment, the total daily dose of the compound of the invention is from about 0.1 to about 50 mg / kg, and in another embodiment, from about 0.5 to about 30 mg / kg. (ie, mg of compound of the invention per kg of body weight). In one embodiment, the dose is 0.01 to 10 mg / kg / day. In another embodiment, the dose is 0.1 to 1.0 mg / kg / day. The dose unit compositions may contain the quantities or submultiples necessary to obtain the daily dose. In several cases, the administration of the compound will be repeated multiple times during a day (in general, no more than 4 times). If desired, in general, multiple doses may be used per day to increase the total daily dose.

For oral administration, the compositions may be provided in the form of tablets containing from about 0.01 mg to about 500 mg of active ingredient or, in another embodiment, from about 1 mg to about 100 mg of active ingredient. Intravenous doses may vary from about 0.1 to about 10 mg / kg / minute during a constant speed infusion.

Suitable subjects according to the present invention include mammals. Mammals according to the present invention include, among others, canines, felines, bovines, goats, equines, sheep, pigs, rodents, lagomorphs, primates and the like, and include mammals in the uterus. In one embodiment, suitable subjects are human beings. Human subjects can be of any gender and can be found at any stage of development.

In another embodiment, the invention comprises the use of one or more compounds of the invention for the preparation of a medicament for the treatment of the conditions indicated herein.

For the treatment of the conditions referred to above, the compound of the invention can be administered as a compound

-37per se. Alternatively, pharmaceutically acceptable salts are suitable for medical applications due to their greater water solubility with respect to the compound of origin.

In another embodiment, the present invention comprises pharmaceutical compositions. The pharmaceutical compositions comprise a compound of the invention presented with a pharmaceutically acceptable carrier. The carrier may be a solid, a liquid or both, and may be formulated with the compound as a unit dose composition, for example, a tablet, which may contain from 0.05% to 95% by weight of the active compounds. A compound of the invention can be coupled with suitable polymers as carriers of addressable drugs. Other pharmacologically active substances may also be present.

The compounds of the present invention can be administered by any acceptable route, preferably, in the form of a pharmaceutical composition adapted to said route and in an effective dose for the intended treatment. For example, active compounds and compositions can be administered orally, rectally, parenterally or topically.

Oral administration of a solid dosage form can be presented, for example, in differentiated units, such as hard or soft capsules, pills, seals, pills or tablets; each contains a predetermined amount of at least one compound of the present invention. In another embodiment, oral administration may be in the form of a powder or granule. In another embodiment, the oral dosage form is sublingual, for example, a pill. In such solid dosage forms, in general, the compounds of Formula I are combined with one or more adjuvants. Said capsules or tablets may contain a controlled release formulation. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents or may be prepared with enteric coatings.

In another embodiment, oral administration may be in the form of a liquid dose. Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, containing inert diluents that are commonly used in the art (eg, water). Such compositions can also

-38 understand adjuvants, such as wetting, emulsifying, suspending, flavoring (for example, sweeteners) and / or perfuming agents.

In another embodiment, the present invention comprises a parenteral dosage form. Parenteral administration includes, for example, subcutaneous injections, intravenous injections, intraperitoneal injections, intramuscular injections, intrasternal injections and infusion. Injectable preparations (eg, injectable sterile aqueous or oleaginous suspensions) may be formulated in accordance with the known art using dispersing, wetting and / or suspending agents.

In another embodiment, the present invention comprises a topical dosage form. Topical administration includes, for example, transdermal administration, such as transdermal patches or iontophoresis devices, infraocular administration or intranasal or inhalation administration. Compositions for topical administration also include, for example, topical gels, sprays, ointments and creams. A topical formulation may include a compound that improves the absorption or penetration of the active ingredient through the skin or other affected areas. When the compounds of the present invention are administered by a transdermal device, administration is achieved with a patch of the porous and reserve membrane type or a variety of solid matrices. Typical formulations for this include gels, hydrogels, lotions, solutions, creams, ointments, dusts, foams, foams, films, dermal patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated; see, for example, J. Pharm Sci., 88 (10), 955-958, by Finnin and Morgan (October 1999).

Formulations suitable for topical administration in the eye include, for example, eye drops, wherein the compound of the present invention is dissolved or suspended in a suitable carrier. A typical formulation suitable for ocular or aural administration may be presented in the form of drops of a suspension or micronized solution in sterile saline solution with a pH adjusted. Other formulations suitable for ocular and ear administration include ointments, biodegradable implants (eg, gel sponges

-39absorbent, collagen) and non-biodegradable (for example, silicone), wafers, lenses and particle or vesicular systems, such as niosomes or liposomes. A polymer, such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer, for example, hydroxypropylmethylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer, for example, gellan gum, can be incorporated together with a preservative, such as chloride Benzalkonium The formulations can also be administered by iontophoresis.

For intranasal or inhalation administration, the active compounds of the invention are conveniently supplied in the form of a solution or suspension from a pump sprayer vessel that the patient presses or pumps, or as an aerosol sprayer from a pressurized container or a nebulizer, with the use of a suitable propellant. Generally, formulations suitable for intranasal administration are administered in the form of dry powder (either alone, as a mixture, for example, in a dry mixture with lactose, or as a particle with mixed components, for example, mixed with phospholipids, such as phosphatidylcloline) from a dry powder inhaler or as an aerosol sprayer from a pressurized container, pump, sprayer, atomizer (preferably, an atomizer that uses electrohydrodynamic to produce a fine mist) or nebulizer, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane . For intranasal use, the powder may comprise a bloadhesive agent, for example, chitosan or cyclodextrin.

In another embodiment, the present invention comprises a rectal dosage form. Said rectal dosage form may take the form, for example, of a suppository. Cocoa butter is a traditional suppository base, but several alternatives can be used as appropriate.

Other carrier materials and modes of administration known in the pharmaceutical art can also be used. The pharmaceutical compositions of the invention can be prepared by any known pharmacy technique, such as effective formulation and administration procedures. The above considerations on effective formulations and administration procedures are known in the art and are described in standard textbooks. Drug formulation is described, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman et al., Eds.,

-40 Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Kibbe et al., Eds., Handbook of Pharmaceutical Excipients (3.^to Ed.), American Pharmaceutical Association, Washington, 1999.

The compounds of the present invention can be used alone or in combination with other therapeutic agents for the treatment of various disease conditions or stages. The compounds of the present invention and other therapeutic agents can be administered simultaneously (either in the same dosage form or in separate dosage forms) or sequentially.

The two or more compounds can be administered simultaneously, concurrently or sequentially. In addition, simultaneous administration can be performed by mixing the compounds before administration, administering the compounds at the same time but in different anatomical locations or using different routes of administration.

The phrases "concurrent administration", "co-administration", "simultaneous administration" and "administered simultaneously" mean that the compounds are administered in combination.

The present invention includes the use of a combination of an IRAK inhibitor compound provided in the compound of Formula I and one or more additional pharmaceutically active agents. If a combination of active agents is administered, they can be administered sequentially or simultaneously, in separate dosage forms or combined in a single dosage form. Accordingly, the present invention also includes pharmaceutical compositions comprising an amount of: (a) a first agent comprising a compound of the Formula I or a pharmaceutically acceptable salt of the compound; (b) a second pharmaceutically active agent; and (c) a pharmaceutically acceptable carrier, vehicle or diluent.

The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents. The terms administered in combination or combination therapy refer to a compound of the present invention and one or more additional therapeutic agents being administered concurrently to the mammal being treated. When administered in combination, each component can be administered at the same time or sequentially in any order, at different time points.

-41Therefore, each component can be administered separately, but close enough in time to provide the desired therapeutic effect. Therefore, the prevention and treatment methods described herein include the use of combination agents.

The combination agents are administered to a mammal, which includes a human being, in a therapeutically effective amount. The term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered alone or in combination with an additional therapeutic agent to a mammal, is effective in treating the desired disease / condition, for example, a condition. inflammatory, such as systemic lupus erythematosus. See also, T, Koutsokeras and T. Heaiy, Systemic lupus erythematosus and lupus nephritis, Nat Rev Drug Discov, 2014, 13 (3), 173-174, for therapeutic agents useful for the treatment of lupus.

In particular, it is contemplated that the compounds of the invention can be administered with the following therapeutic agents:

Nonsteroidal anti-inflammatory drugs (NSAIDs), which include, but are not limited to, non-selective COX1 / 2 inhibitors, such as piroxlcam, naproxen, flublprofen, fenoprofen, ketoprofen, ibuprofen, etodolac (Lodine), mephanazone, pyindazolone (sulindaconas) such as phenylbutazone), salicylates (such as aspirin); Selective COX2 inhibitors, such as: celecoxib, rofecoxib, etoricoxib, valdecoxib, meloxicam;

Immunomodulatory and / or anti-inflammatory agents, including, but not limited to, methotrexate, lefiunomide, clciesonide, chloroquine, hydroxychloroquine, dpeniciliamine, auranofin, sulfasalazine, sodium aurothiomalate, cyclosporine, azathioprlne, cromolomethyl fumarate, monolithoamide, monolimide, fumarate and dimethyl), glatiramer acetate, mitoxantrone, teriflunomlde, suplatast tosylate, mycophenolate mofetil and cyclophosphamide, laquinimod, voclosporin, PUR118, AMG 357, AMG 811, BCT197;

Antimalarials, including but not limited to hydroxychloroquine (Plaquenil) and chloroquine (Aralen), cyclophosphamide (Cytoxan), methotrexate (Rheumatrex), azathioprine (imuran), mesalamlne (Asacol) and sulfasalazine (Azulfidine):

Antibiotics, which include, among others, Flagyi or ciprofloxacin;

-42 Anti-TNFa agents, including but not limited to infliximab, adalimumab, certoiizumab pegol, goiimumab and etanercept;

Anti-CD20 agents, which include, among others, rituximab, ocreiizumab, ofatumumab and PF-05280586;

Antidiarrheals, such as diphenoxylate (Lomotil) and ioperamide (Imodium);

Bile acid binding agents, such as cholestyramine, aiosetron (Lotronex) and ubiprostone (Amitiza);

Laxatives, such as milk of magnesia, polyethylene glycol (MiraLax), Dulcolax, Correctol and Senokot, and anticholinergics or antispasmodics, such as dicyclomine (Bentyl);

T lymphocyte activation inhibitors, which include, but are not limited to, abatacept:

Anti-iL1 treatments, which include, among others, anakinra, rilonacept, canakinumab, gevokizumab, MABpl and MEDI-8968;

Glucocorticoid receptor modulators that can be administered orally, inhalation, injection, topically, rectally, or by ocular administration, including, but not limited to, betamethasone, prednisone, hydrocortisone, prednisolone, flunisolide, triamcinoline acetonide, beclomethasone, dipropionate , budesonide, fluticasone propionate, ciclesonide, mometasone furoate, fluocinonide, deoximetasone, methylprednisolone or PF-04171327;

Aminosalicylic acid derivatives, including, but not limited to, sulfasalazine and mesalazine;

Anti-a4 integrin agents, which include, among others, natalizumab;

A1- or A2-adrenergic agonist agents, including, but not limited to: propylhexidrine, phenylephrine, phenylpropanolamine, pseudoephedrine or nafazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride or hydropinephrinerate hydrochloride;

Β-adrenergic agonists, which include, among others, metaproterenol, isoprotenerol, soprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, botolterol mesylate, pirbuterol;

Anticholinergic agents, including, but not limited to, ipratropium bromide, tiotropium bromide, oxypropium bromide, aclindinium bromide, glycopyrrolate, pyrenzipine or telencepine;

-43Beta-long-acting agonists Inhaled, long-acting muscarinic antagonists and long-acting corticosteroids, which include, among others, those included in the following reference: Y. Mushtaq, The COPD plpellne, Nat Rev Drug Discov, 2014, 13 ( 4), 253-254. http://dx.dol.Org/10,1038/nrd425;

Leukotriene pathway modulators, which include, among others, 5-LO inhibitors (such as zileuton), FLAP antagonists (such as veliflapon, fiboflapon), LTD4 antagonists (such as montelukast, zafirlukast or pranlukast;

H1 receptor antagonists, which include, among others, cetlrlzlne, loratldlne, desloratldine, fexofenadlne, astemlzole, azelastlne or chlorphenlramine;

PDE4 inhibitors, which include, among others, apremllast, roflumllast or AN2728;

Vitamin D receptor modulators, which include, among others, paricalcitol;

Activators of the aNrf2 pathway, which include, among others, fumarates, sulfurophane and bardoxolone methyl;

Modulators of the orphan receptor family related to RAR (ROR), in particular, RORg;

Chemokine receptor modulator and / or antagonists, which include, among others, CCR2 antagonists (such as CCX140, BMS-741672, PF-4634817, CCX-872, NOX-E36), CCR2 / 5 antagonists ( such as PF-4634817), CCR9 (such as verclmon, CCX507), CCR1 modulators, CCR4 modulators, CCR5 modulators, CCR6 modulators, CXCR6 modulators, CXCR7 modulators) and CXCR2 modulators (such as danirlxln, AZD5069l, AZD5069l );

Prostaglandlnas, which include, among others, prostacyclln;

PDE5 inhibitors, which include, but are not limited to, slldenafll, PF-489791, vardenafil and tadalafll;

Endothelin receptor antagonists, which include, among others, bosentan, ambrisentan, sparsentan, atrasentan, zibotentan and macitentan;

Soluble guanllate clclase activators, which include, among others, rioclguat;

Interferons, which include, but are not limited to, Interferon beta-1a, Interferon beta-1b;

Epingosine 1-phosphate receptor modulators, which include, among others, flngollmod, ponesimod;

-44 Complementary pathway inhibitors, including but not limited to C5aR antagonists (such as CCX168, PMX-53, NN8210), C5 inhibitors (such as eculizumab), inhibitors of complementary factors B and D, MASP2 inhibitors ( such as OMS-721) and ARC-1905;

Janus qulnasas inhibitors (one or more of JAK1, JAK2, JAK3, TYK2), which include, but are not limited to, decernotinlb, cerdulatlnib, JTE-052, ruxolltinlb, tofacitnib, Baricltiníb, Peflcltlnlb, GLPG-0634, INCB-0698, INCB-0698, INCB-06-986 039110, PF-04965842, XL-019, ABT-494, R-348, GSK-2586184, AC-410, BMS-911543 and PF-06263276;

Inhibitors of other anti-inflammatory kinase or immunomodulatory kinases, which include, among others, splenic tyrosine kinase inhibitors (SYK), p38 MAP kinase inhibitors (such as PF-3715455, PH-797804, AZD-7624, AKP-001, UR13870, FX-005, semapimod, pexmetlnib, ARRY-797, RV-568, dllmaplmod, rallmetínlb), PI3K inhibitors (such as GSK-2126458, pilaralisib, GSK-2269557), PI3Kg and / or PI3Kd inhibitors (such as CAL- 101 / GS-1101, duvellslb), JNK inhibitors, ERK1 and / or 2 inhibitors, IKKb inhibitors, BTK inhibitors, ITK inhibitors, ASK1 inhibitors (such as GS-4997), PKC inhibitors (such as sotrastaurin), TrkA antagonists (such as CT-327) , MEK1 inhibitors (such as E6201);

Antioxldantes, that include, among others, inhibitors of mleloperoxldasa (such as AZD-3241), NOX4 and other NOX enzymes (such as GKT-137831) and Nacetilcisteína;

IL5 inhibitors, which include, among others, mepolizumab, reslizumab and benrallzumab;

IL4 inhibitors, which include, among others, pascolizumab, altrakincept and pitrakinra;

IL13 inhibitors, which include, among others, tralokinumab, anrukinzumab and lebrikizumab;

Anti-IL6 agents, which include, among others, tocilizumab, olokizumab, slltuxlmab, PF-4236921 and slrukumab;

IL17 / IL17R inhibitors / antagonists, which include, but are not limited to, secukinumab, RG-7624, brodalumab and ixekizumab;

Antagonists of IL12 and / or IL23, which include, among others, tildrakizumab, guselkumab, MEDI2070 and AMG 139;

1L33 inhibitors, which include, among others, AMG 282;

IL9 inhibitors, which include, among others, MEDI-528;

GM-CSF inhibitors, which include, among others, MT203;

Anti-CD4 agents, which include, among others, tregalizumab and rigerimod;

CRTH2 antagonists, which include, among others, AZD-1981;

B lymphocyte stimulator inhibitors (BLYS; also known as BAFF), a protein that frequently increases in patients with SLE, including, but not limited to, belimumab, tabalumab, blisibimod and atacicept;

Monoclonal antibodies specific for CD22, which include, among others, epratuzumab;

Interferon-α inhibitors, which include, among others, sifalimumab and rontalizumab;

Inhibitor of type I interferon receptors, which includes, among others, MEDI546;

FcyRIIB agonists, which include, among others, SM-101;

Modified and / or recombinant versions of the thermal shock protein 10 (Hsp10, also known as chaperonin 10 or EPF), which include, among others,

INV-103;

TNF 12A superfamily receptor inhibitors (TWEAK receptor), which include, among others, BIIB-023, enavatuzumab and RG-7212;

Xanthine oxidase inhibitors, which include, among others, allopurinol, benzbromarone, febuxostat, topiroxostat, tisopurine and inositols;

URAT1 inhibitors (also known as SLC22A12), which include, among others, lesinurad, RDEA 3170, UR1102 and levotofispam;

Additional treatments for gout and / or to reduce uric acid levels, including, but not limited to, colchicines, pegloticase, benciodarone, isobrominidione, BCX4208 and arhalofenate;

Toll-like receptor (TLR) inhibitors, which include, among others, one or more of TLR7, TLR8, TLR9 (such as IMO-8400, ΙΜΘ-3100, DV-1179), TLR2 and / or TLR 4 (such as VB-201, OPN-305);

TLR agonists, which include, among others, TLR7 (such as GSK2245035, AZD8848), TLR9 (such as AZD1419);

Activators of SIRT1, which include, among others, SRT2104;

-46 A3 receiver agonists, which include, among others, CF101;

Other agents for the use of psoriasis treatment, including but not limited to IDP-118, LAS41004, LEO 80185, LEO 90100, PH-10, WBI-1001, CNT01959, BT-061, cimzia, ustekinumab, MK-3222 / SCH 900222, ACT-128800, AEB071, alitretinoin, ASP015K, Apo805K1, BMS-582949, FP187, hectoral (doxercalciferoi), LEO 22811, Ly3009104 (INCB28050), calcipotriene foam (STF 115469), tofacitinib (CP690510150) and CycloPsorb ™;

Antifibrotic agents, including but not limited to: pirfenidone, LOXL2 inhibitors (such as Simtuzumab), FT-011, epirregulin modulators and / or TGFa (such as LY-3016859), TGFp modulators (such as LY-2382770, fresolimumab );

Prolylhydroxylase inhibitors, which include, among others, GSK1278863, FG2216, ASP-1517 / FG-4592, AKB-6548, JTZ-951, BAY-85-3934 and DS-1093;

Inhibitors of granulocyte and macrophage colony stimulating factor, including but not limited to GSK3196165 (MOR103), PD-0360324 and mavrilimumab;

Inhibitors of MAdCAM and / or integrin α4β7, which include, among others, PF00547659 and MEDI7183 (Aprilumab);

Inhibitors of connective tissue growth factor (CTGF), which include, among others, PF-06473871; cathepsin C inhibitors, which include, among others, GSK2793660;

Soluble epoxide hydrolase inhibitors, which include, among others, GSK2269557;

TNFR1-associated death domain protein inhibitors, which include, among others, GSK2862277;

Anti-CD19 agents, which include, among others, MEDI-551 and AMG 729;

Anti-B7RP1 agents / ICOS ligand inhibitors, including, but not limited to, MEDI5872 and AMG-557;

thymic stromal lymphoprotein inhibitors, which include, among others, AMG157;

IL2 inhibitors, which include, among others, daclizumab;

6A leucine-rich neuronal repeat protein inhibitors, including, but not limited to, Anti-Line (Biogen);

-47 Integrin inhibitors, including but not limited to alpha-V / beta-6 (STX-100) and alpha-V / beta-3 (VPI-2690B);

Anti-CD40L agents, which include, among others, CDP-7657;

Dopamiña D3 receptor modulators, which include, among others, ABT-614;

Galectin-3 inhibitors and / or modulators, which include, among others, GCS-100 and GR-MD-02;

Agents for the treatment of diabetic nephropathy, including, but not limited to, DA-9801 and ASP-8232;

Agents for the treatment of acute renal injury, including, among others, THR-184, TRC-160334, NX-001, EA-230, ABT-719, CMX-2043, BB-3 and MTP-131;

Inflammasome modulators, which include, among others, NLRP3 inhibitors;

Bromodomain modulators, which include, among others, BRD4;

GPR43 modulators; and

TRP channel inhibitors, which include, among others, TRPA1, TRPC3, TRPC5, TRPC6 and TRPC6.

Additional therapeutic agents include antlcoagulants or coagulation inhibitors, antiplatelet or platelet inhibitors, thrombin, thrombolytic or fibrinolytic inhibitors, antiarrhythmics, antihypertensors, calcium channel blockers (type L and type T), cardiac glycosides, diuretics, antagonists mineralocorticoid receptor, NO donating agents, such as organoniites, NO promoting agents, such as phosphodiesterase inhibitors, hlpocolesterolemiants / lipid-lowering agents and lipid profile therapies, antidiabetics, antidepressants, anti-inflammatories (steroids and non-steroids), antiosteoporotics, hormone replacement therapies, oral contraceptives, obesity agents, anxiolytics, antiproliferatives, anti-ulcers and anti-ulcer agents gastroesophageal reflux, growth hormone and / or growth hormone secretagogues, Thyroid mimetics (which includes the thyroid hormone receptor antagonist), anti-infectives, anti-viral, anti-bacterial and anti-fungal agents.

Agents used in the intensive care unit (ICU) are included, for example, dobutamine, dopamine, epinephrine, nitroglycerin, nitroprusside, etc.

-48 Combination agents useful for the treatment of vasculitis are included, for example, azathioprine, cyclophosphamide, mycophenolate, mofetil, rituximab, etc.

In another embodiment, the present invention provides a combination wherein the second agent is at least one agent selected from a factor Xa inhibitor, an anticoagulant, an antiplatelet, a thrombin inhibitor, a thrombolytic and a fibrinolytic. Example factor Xa inhibitors include apixaban and rivaroxaban. Examples of suitable anticoagulants for use in combination with the compounds of the present invention include heparins (eg, unfractionated and low molecular weight heparins, such as enoxaparin and dalteparin).

In another embodiment, the second agent is at least one agent selected from warfarin, unfractionated heparin, low molecular weight heparin, synthetic pentasaccharides, hirudin, argatrobanas, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac , sulfinpyrazone, piroxicam, ticlopidine, clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase and streptokinase.

In another embodiment, the agent is at least one antiplatelet agent. Antiplatelet agents of particular preference are aspirin and clopidogrel. As used herein, antiplatelet agents (or platelet inhibitors) refers to agents that inhibit platelet function, for example, by inhibiting platelet aggregation, adhesion or secretion. Agents include, among others, several known non-spheroidal anti-inflammatory agents (NSAIDs), such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, and salts or prodrugs thereof acceptable from the point of Pharmaceutical view Of the NSAIDs, aspirin (acetylsalicylic acid or ASA) and COX-2 inhibitors, such as celecoxib or piroxicam, are preferred. Other suitable platelet inhibitors include llb / llla antagonists (for example, tirofiban, eptifibatide and abciximab), thromboxane A2 receptor antagonists (for example, ifetroban), thromboxane-A2 synthetase inhibitors, PDE-III inhibitors (for example, Pletal, dlpyridamole), and pharmaceutically acceptable salts or prodrugs thereof.

-49 As used herein, the term "antiplatelet agents (or platelet inhibitors") also includes antagonists of the ADP receptor (adenosine diphosphate), preferably, purinergic receptor antagonists P2Y-1 and P2Y12I P2Y12 ^{it is} more preferably. Preferred P2Y12 receptor antagonists include ticagrelor, prasugrel, ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Clopidogrel is a more preferred agent. The compounds ticlopidine and clopidogrel are also preferred, because they do not cause damage to the gastrointestinal tract.

As used herein, the term thrombin inhibitors (or thrombin agents) refers to inhibitors of serine protease thrombin. By inhibiting thrombin, several thrombin-mediated processes are interrupted, such as thrombin-mediated platelet activation (i.e., for example, platelet aggregation and / or granular secretion of plasminogen activator inhibitor 1 and / or serotonin) and / or fibrin formation. The people of the medium level trade know several thrombin inhibitors, and the use of these inhibitors in combination with the compounds herein is contemplated. These inhibitors include, among others, derivatives of boroarglnine, boropeptides, heparlnas, hirudin, argatroban and melagatran, including the pharmaceutically acceptable salts and prodrugs thereof. Boroarginine and boropeptide derivatives include peptide and N-acetyl derivatives of boronic acid, such as lysine, ornithine, alpha-aminoboronic acid C-terminal derivatives of arginine, homoarginine and corresponding sotiouronlo analogs. As used herein, the term hirudin includes suitable analogs or derivatives of hirudin, referred to herein as hirologists, such as disulfatohirudin. As used herein, the term "thrombolytic or fibrinolytic (or thrombolytic or fibrinolytic) agents" refers to agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator (natural or recombinant) and modified forms thereof, anistrepiase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), Vlla factor inhibitors, PAI-1 inhibitors (i.e. tissue plasminogen activator inhibitor nactivators), alpha inhibitors

2-antipIasmlna and anlsoylated plasminogen / streptokinase activator complex, including pharmaceutically acceptable salts and prodrugs. As used herein, the term "anistrepiase" refers to i

-50 anisolated plasminogen activator / streptokinase complex, as described, for example, in EP 028,489 ,. As used herein, the term urokinase refers to the double stranded and single stranded urokinase, the latter is also referred to as prourokinase in the present. Examples of suitable antiarrhythmic agents include: Class I agents (such as propafenone); Ciase il agents (such as metoprolol, atenolol, carvadiol and propranoiol); Class III agents (such as sotalol, dofetilide, amiodarone, azimilide and ibuttlide); Class IV agents (such as ditiazem and verapamil); K channel openers⁺, such as i / \ inhibitors_Ci have l ^ inhibitors_ur (for example, compounds such as those described in W001 / 40231).

The compounds of the present invention can be used in combination with antihypertensives, and the activity against hypertension can easily be determined by persons of the mid-level trade according to standard tests (for example, blood pressure measurements). Examples of suitable antihypertensive agents include alpha adrenergic blockers; beta adrenergic blockers; calcium channel blockers (for example, diltiazem, verapamil, nifedipine and amlodipine); vasodilators (eg hydraiazine), diuretics (eg, chiorothiazide, hydrochiorothiazide, fiumethiazide, hydroflumethíazide, bendrofiumethiazide, methylchlorothiazide, trichloromethiazide, polythíazide, benzthiazide, ethacrynic acid, tricrynafen, chlorthalidone, torsemide, furosemide, musolimine, bumetanide, triamtrenene, amiioride, spironolactone); renin inhibitors; ACE inhibitors (for example, captopril, zofenoprii, fosinopril, enalapril, ceranoprii, ciiazopril, delapril, pentopril, quinapril, ramipril, lisinopril); AT-1 receptor antagonists (eg, losarran, irbesartan, waltz); ET receptor antagonists (for example, sitaxsentan, atrsentan and the compounds described in US Pat.^you 5,612,359 and 6,043,265); dual ET / AII antagonist (for example, the compounds described in WO 00/01389); neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors) (for example, gemopatrilat and nitrates). An example of an antianginal agent is ivabradine.

Examples of suitable calcium channel blockers (type L or type T) include diltiazem, verapamil, nifedipine, amlodipine and mybefradii. Examples of suitable cardiac glycosides include digitalis and ouabain.

-51 In one embodiment, a compound of the invention can be co-administered with one or more diuretics. Examples of suitable diuretics include (a) loop diuretics, such as furosemlda (such as LASIX ™), torsemide (such as DEMADEX ™), bemetanlda (such as BUMEX ™) and ethacrynic acid (such as EDECRIN ™); (b) thiazide-type diuretics, such as chlorothiazide (such as DIURIL ™, ESIDRIX ™ or HYDRODIURIL ™), hydrochlorothiazide (such as MICROZIDE ™ or ORETIC ™), benzthiazide, hldroflumethiazide (such as SALURON ™), bendroflumethiazidazidate, zalzidazidazidate trichlormetlazide and indapamide (such as LOZOL ™); (c) phthalimidine diuretics, such as chlorthalidone (such as HYGROTON ™) and metolazone (such as ZAROXOLYN ™); (d) qulnazoline type diuretics, such as quinetazone; and (e) potassium moderating diuretics, such as triamterene (such as DYRENIUM ™) and amiloride (such as MIDAMOR ™ or MODURETIC ™). In another embodiment, a compound of the invention can be co-administered with a loop diuretic. In yet another embodiment, the loop diuretic is selected from furosemide and torsemide. In yet another embodiment, one or more compounds of the invention can be co-administered with furosemide. In yet another embodiment, one or more compounds of the invention can be co-administered with torsemide which, optionally, can be a controlled or modified form of torsemide release.

In another embodiment, a compound of the invention can be co-administered with a thiazide-type diuretic. In yet another embodiment, the thiazide type diuretic is selected from the group consisting of chlorothiazide and hydrochlorothiazide. In yet another embodiment, one or more compounds of the invention can be co-administered with chlorothiazide. In yet another embodiment, one or more compounds of the invention can be co-administered with hydrochlorothiazide. In another embodiment, one or more compounds of the invention can be co-administered with a phthalimidine diuretic. In yet another embodiment, the phthalimidine diuretic is chlorthalidone.

Examples of suitable combinations of mineralocorticoid receptor antagonists include sprionolactone and eplerenone. Examples of suitable combinations of phosphodiesterase inhibitors include; PDE III inhibitors (such as cilostazol); and PDE V inhibitors (such as sildenafil).

-52 The compounds of the present invention can be used in combination with cholesterol modulating agents (including hypocholesterolemic agents), such as a lipase inhibitor, an HMG-CoA reductase inhibitor, an HMG-CoA synthase inhibitor, an inhibitor of HMG-CoA reductase gene expression, an inhibitor of HMG-CoA synthase gene expression, an inhibitor of MTP / Apo B secretion, an inhibitor of CETP, an inhibitor of bile acid absorption, a cholesterol absorption inhibitor, a cholesterol synthesis inhibitor, a squalene synthetase inhibitor, a squalene epoxidase inhibitor, a squalene cyclase inhibitor, a combined squalene epoxidase / squalene cyclase inhibitor, a fibrate, niacin, a Ion exchange resin, an antioxidant, an ACAT inhibitor, a bile acid sequestrant or an agent, such as mipomersen.

Examples of suitable hypocholesterolemiants / lipid-lowering agents and lipid profile therapies include: HMG-CoA reductase inhibitors (eg pravastatin, lovastatin, atorvastatin, simvastatin, fluvastatin, NK-104 (also known as itavastatin, nisvastatin or nisbastatin) -4522 (also known as rosuvastatin, atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants (such as questran); ACAT inhibitors; MTP inhibitors; lipoxygenase inhibitors; cholesterol absorption inhibitors; and cholesterol transfer protein inhibitors.

Anti-inflammatory agents also include sPLA2 and lpPLA2 inhibitors (such as darapladlb), 5-LO inhibitors (such as atrelueton) and IL-1 and IL-1 r antagonists (such as canakinumab).

Other atherosclerotic agents include agents that modulate the action of PCSK9, for example, called bococlzumab.

Cardiovascular complications of type 2 diabetes are associated with harmful levels of MPO; consequently, the compounds of the present invention can be used in combination with anti-diabetes agents, in particular anti-type 2 diabetes agents. Examples of suitable anti-diabetes agents include (for example, insulins, metphomine, DPPIV inhibitors, GLP-1 agonists, analogs and mimetics, inhibitors of SGLT1 and SGLT2). Suitable anti-diabetes agents include an acetyl-CoA carboxylase (ACC) inhibitor, such as ios described in W02009144554, W02003072197, W02009144555 and W02008065508, a diacylglycerol O-acyltransferase 1 (DGAT-1) inhibitor, such as

-53 those described in W009016462 or WO2010086820, AZD7687 or LCQ908, diacylglycerol O-acyltransferase 2 (DGAT-2) inhibitors, monoacylglycerol O-acyltransferase inhibitors, a phosphodiesterase (PDE) inhibitor, an AMP activator sulfonylurea (for example, acetohexamide, chlorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquídone, glisolamide, tolazamide and tolbutamide), a meglitinide, an aamylase inhibitor (for example, tendamistat, trestatin and AL-3688), an a-glycoside hydrolase inhibitor (for example, acarbose), an α-glucosidase inhibitor (for example, adiposine, camiglibose, emiglitate, miglitol, voglibose , pradimicin-Q and salbostatin), a PPARy agonist (for example, balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone and rosiglitazone), a PPAR α / γ agonist (for example, CLX0940, GW-1536, GW- 1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB219994), a biguanide (for example, metformin), a glucagon-like peptide modulator (GLP-1), such as an agonist (for example, exendin-3 and exendin-4), liraglutide, albiglutide, exenatide (Byetta®), albiglutide, lixisenatide, dulaglutide, semaglutide, NN-9924, TTP-054, an inhibitor of the tyrosine phosphatase-1B protein (PTP-1B) (for example, trodusquemine and extract of hyst the compounds described in Zhang, S. et al., Drug Discovery Today, 12 (9/10), 373-381 (2007)), SIRT-1 inhibitor (e.g., resveratrol, GSK2245840 or GSK184072), a dipeptidyl peptidease IV (DPP-IV) inhibitor (for example, those described in W02005116014, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin), an insulin secretagogue, an inhibitor of fatty acid oxidation, an A2 antagonist, an amino-terminal inhibitor c-jun kinase (JNK), glucokinase activators (GKa), such as those described in WO2010103437, WO2010103438, WO2010013161, W02007122482, TTP-399, TTP-355, TTP-547, AZD1656, ARRY403, MK-0599, TAK-329, AZD5658 or GKM-001, insulin, an insulin mimetic , a glycogen phosphorylase inhibitor (for example, GSK1362885), a VPAC2 receptor agonist, SGLT2 inhibitors, such as those described in EC Chao et al. Nature Reviews Drug Discovery 9, 551-559 (July 2010), which include dapagliflozin, canagliflozin, empagliflozin, tofogliflozin (CSG452), ASP-1941, THR1474, TS-071, ISIS388626 and LX4211, and those described in WO2010023594, a modulator of the glucagon receptor, such as those described in Demong, DE et al. Annual Reports in Medicinal Chemistry 2008, 43, 119-137, modulators of GPR119, in particular,

-54agonists, such as those described in WO2010140092, WO2010128425,

W02010128414, WO2010106457, Jones, RM et al, in Medicinal Chemistry 2009, 44, 149-170 (for example, MBX-2982, GSK1292263, APD597 and PSN821), derivatives or analogs of FGF21, such as those described in Kharitonenkov, A. et al. et al., Current Opinion in Investigational Drugs 2009, 10 (4) 359-364, TGR5 receptor modulators (also called GPBAR1), in particular, agonists, such as those described in Zhong, M., Current Topics in Medicinal Chemistry , 2010, 10 (4), 386-396 and INT777, agonists of GPR40, such as those described in Medina, JC, Annual Reports in Medicinal Chemistry, 2008, 43, 75-85, which include, among others, TAK-875 , modulators of GPR120, in particular, agonists, high affinity nicotinic acid receptor activators (HM74A) and SGLT1 inhibitors, such as GSK1614235. Another representative list of anti-diabetes agents that can be combined with the compounds of the present invention can be found, for example, from page 28, line 35 to page 30, line 19 of WO2011005611. Preferred anti-diabetes agents are metformin and DPP-IV inhibitors (for example, sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin and saxagliptin). Other anti-diabetes agents may include inhibitors or modulators of carnitine paimitoyl transferase enzymes, fructose 1,6-diphosphatase inhibitors, aldose reductase inhibitors, mineralocorticolde receptor inhibitors, TORC2 inhibitors, CCR2 and / or CCR5 inhibitors, inhibitors of the PKC software (for example, PKCa, ΡΚΟβ, PKCD), fatty acid synthetase inhibitors, serine paimitoyl transferase inhibitors, modulators of GPR81, GPR39, GPR43, GPR41, GPR105, Kv1.3, retinol-binding protein 4, glucocorticoid receptor, somatostain receptors (e.g., SSTR1, SSTR2, SSTR3 and SSTR5), inhibitors or modulators of PDHK2 or PDHK4, inhibitors of MAP4K4, modulators of the family of IL1, including IL1 beta, RXRalfa modulators. In addition, suitable agents against diabetes include the mechanisms listed in Carpino, PA, Goodwin, B. Expert Opin. Ther. Pat, 2010, 20 (12), 1627-51.

People of the mid-level trade will recognize that the compounds of the present invention can also be used in conjunction with other cardiovascular or cerebrovascular treatments that include percutaneous coronary intervention (PCI), stenting, drug eluting stents, cell therapy

-55 mothers and medical devices, such as pacemaker implant, defibrillators or cardiac resynchronization therapy.

The compounds of the present invention can be used in combination with neuroinflammatory and neurodegenerative agents in mammals. Examples of additional neuroinflammatory and neurodegenerative agents include antidepressants, antipsychotics, analgesics, agents against Alzheimer's disease and anxiolytics. Examples of particular classes of antidepressants that can be used in combination with the compounds of the invention include norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs), NK-1 receptor antagonists, monoamlna oxldasa inhibitors (MAOI), Reversible monoamlna oxidase inhibitors (RIMA), serotonin and noradrenallna reabsorption inhibitors (SNRI), corticotropin release factor antagonists (CRF) and atypical antidepressants. Suitable norepinephrine reabsorption inhibitors include tricyclic tertiary amines and tricyclic secondary amines. Examples of suitable tricyclic tertiary amines and suitable tricyclic secondary amines include amitriptyline, clomipramine, doxepin, mipramine, trlmlpramine, dothiepin, butriptyline, nortriptyline, protriptyline, amoxapine, desipramine and maprotiline. Examples of suitable SSRIs include fluoxetine, fluvoxamine, paroxetine and sertraline. Examples of monoamlna oxidase inhibitors include ¡socarboxazid, phenelzine and tranylcyclopramlne. Examples of suitable reversible inhibitors of monoamine oxidase include moclobemide. Examples of SNRI suitable for use in the present invention include venlafaxine. Examples of suitable atypical antidepressants include bupropion, lithium, trazodone and viloxazine. Examples of agents against Alzheimer's disease include NMDA receptor antagonists, such as memantine; and cholinesterase inhibitors, such as donepezil and galantamine. Examples of suitable anxiolytic classes that can be used in combination with the compounds of the invention include benzodiazepines, serotonin 1A receptor agonists (5HT1A) and CRF antagonists. Suitable benzodiazepines include alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, lorazepam, oxazepam and prazepam. Suitable 5-HT1A receptor agonists include buspirone and ipsapirone. Suitable CRF antagonists include verucerfont. Suitable atypical antipsychotics include paliperidone, zlprasidone, risperidone,

-56aripiprazole, olanzapine and quetiapine. Suitable nicotinic acetylcholine agonists include CP-601927 and varenicline. Painkillers include pregabalin, gabapentin, clonidine, neostigmine, baclofen, midazolam, ketamine and ziconotide.

The present invention also comprises kits that are suitable for use in the treatment methods described above. In one embodiment, the kit contains a first dosage form comprising one or more of the compounds of the present invention and a dose container, in amounts sufficient to perform the methods of the present invention.

In another embodiment, the kit of the present invention comprises one or more compounds of the invention.

The present invention also comprises intermediary compounds useful in the synthesis of the compounds of the invention, including salts and / or tautomers thereof.

General Synthesis Schemes

The compounds of the Formula I can be prepared with the methods described below, together with the methods of synthesis known in the state of the art of organic chemistry, or modifications and transformations known to the people of the medium level trade. The starting materials used herein are commercially available or can be prepared by routine methods known in the art [such as the methods described in the standard reference books, for example, Compendium of Organic Synthetic Methods, Vol IXII (published by Wiley-Interscience)]. Preferred methods include, but are not limited to, those described below.

During the following synthesis sequences it may be necessary and / or desirable to protect sensitive or reactive groups in any of the molecules in question. This can be achieved by conventional protecting groups, such as those described in TW Greene, Protective Groups in Organic Chemistry, John Wiley &amp; Sons, 1981; TW Greene and PGM Wuts, Protective Groups in Organic Chemistry, John Wiley &amp; Sons, 1991, and TW Greene and PGM Wuts, Protective Groups in Organic Chemistry, John Wiley &amp; Sons, 1999, The compounds of Formula I, or their pharmaceutically acceptable salts, can be prepared according to the Reaction Schemes

-57 · described hereinbelow. Unless otherwise indicated, the substituents in the schemes are those defined above. The isolation and purification of the products are achieved by standard procedures known to a chemist with knowledge in the art.

The person skilled in the art will understand that the various symbols, superscripts and subscripts that are used in the schemes, methods and examples are to facilitate representation and / or reflect the order in which they are introduced in the schemes; they do not necessarily correspond to the symbols, superscripts or subscripts of the appended claims. Additionally, a person of the medium level trade will recognize that, in many cases, these compounds will be mixtures and enantiomers that can be separated at different stages of the synthesis schemes using conventional techniques, such as crystallization, normal phase chromatography, chromatography reverse phase and chiral chromatography, to obtain simple enantiomers. The schemes represent the methods useful for synthesizing the compounds of the present invention. They do not limit the scope of the invention in any way.

Scheme 1

<img file="CU20160149A7_D0007.tif" />

<img file="CU20160149A7_D0008.tif" />

Additional stages (optional) (R⁸) v 9 .R²

<img file="CU20160149A7_D0009.tif" />

Scheme 1 illustrates a method for the preparation of compounds of Formula la. A compound of Formula A, wherein Lv is a displaced leaving group (such as chlorine or fluoro), is treated with a compound of Formula B (for example, see Scheme 9, or as commercially available) to obtain a product of Formula la. In general, the reaction is carried out in the presence of a suitable base, such as cesium carbonate, potassium tert-butoxide, sodium hydride or potassium hexamethyldisilazide in a suitable solvent or a mixture of solvents, such as THF or dimethylformamide. The compounds of Formula A can be prepared as described in the following schemes. The compounds of Formula R²-OH can be obtained from commercial suppliers, or

-58 can be prepared by methods reported in the chemical literature, or they can be prepared as described in the following schemes.

If desired, additional transformations can be performed on the compound of Formula la. For example, the compound of Formula la in which R⁶ = CN can be subjected to a nitrile hydrolysis reaction to obtain a compound of Formula la wherein R⁶ = CONH₂. The reaction can be carried out in several ways known by the person of the medium level trade, for example, by the use of acids or bases, optionally, in the presence of an oxidant, such as hydrogen peroxide, or by the use of enzymatic catalysts. or chemicals In other cases, the compound of the Formula can also be treated with reagents, such as acids, to cleave protective groups, such as t-butoxycarbonyl groups, and / or with other reagents to derivatize functional groups, such as carboxyl groups, amino or hydroxyl.

<img file="CU20160149A7_D0010.tif" />

<img file="CU20160149A7_D0011.tif" />

(R®) and

Additional stages (optional)

R¹ .OR.

R⁶

<img file="CU20160149A7_D0012.tif" />

(R^S)Y

Scheme 2 illustrates another method for the preparation of compounds of Formula la, particularly suitable for those cases where X and Y in the compound of Formula A are carbons. This method provides the alkylation a compound of Formula A with a compound of Formula B (wherein the group R¹²O- is hydroxyl or a sulfonate ester, such as p-toluenesulfonate or methanesulfonate; for example, see Scheme 9, or as commercially available), using methods known to the people of the medium level trade, to obtain a product of Formula la. For example, this reaction can be performed by treating a compound of Formula A with a compound of Formula B (R¹² = H) in the presence of triphenylphosphine and an azodicarboxylate ester ("Mitsunobu reaction") in a suitable solvent, such as THF. Alternatively, the alkylation of a compound of Formula A can be performed by using a compound of Formula B (R¹²O = TsO or other ester

-59 sulfonate) in the presence of a base, such as cesium carbonate, in a suitable solvent, such as THF or dimethylformamide.

If desired, additional transformations can be performed on the compound of Formula la. For example, the compound of Formula la in which R^s = CN can be subjected to a nitrile hydrolysis reaction to obtain a compound of Formula la wherein R^s = CONH₂. The reaction can be carried out in various ways known by the person of the medium level trade, for example, by the use of acids or bases, optionally, in the presence of an oxidant, such as hydrogen peroxide, or by the use of enzymatic catalysts. or chemicals In other cases, the compound of the Formula can also be treated with reagents, such as acids, to cleave protective groups, such as t-butoxycarbonyl groups, and / or with other reagents to derivatize functional groups, such as carboxyl groups, amino or hydroxyl.

Scheme 3

<img file="CU20160149A7_D0013.tif" />

Scheme 3 illustrates a method for the preparation of compounds of Formula A, wherein Y = N and X = CH, as illustrated above. An acid from the

-60 Formula C is treated with an alkylating agent, for example, odomethane (R¹ = methyl), and a base, such as K₂CO₃, in a suitable solvent, such as DMF. The resulting ester of Formula Cii is then reduced to a compound of Formula Ciü by treatment with a suitable reducing agent, such as NaBH₄, in a solvent, such as THF. The alcohol of the Formula Ciii is oxidized to an aldehyde of the Formula Civ using methods known to those of the medium level profession, such as treatment with pyridlium chlorochromate or manganese dioxide. The isoquinoline ring is formed from the aldehyde of the Formula Civ by reaction with an acetal amlnoacetaldehyde and then by treatment with boron trifluoride etherate, as described in Synthetic Communications 1999, 29 (9), p. 1617 The resulting isoquinoline of the Formula Cv is damaged, using methods known to the people of the medium level trade, such as treatment with copper (l) cyanide in a solvent, such as DMF or pyridine, to obtain a nitrile of the Formula Cvi . Oxidation with a suitable oxidizing agent, such as hydrogen peroxide or a peracid, such as m-chloroperbenzoic acid or peracetic acid, produces an isoquinoline N-oxide of the Formula Cvii. This can be halogenated by methods known to medium-level persons, frequently, by treatment with phosphorus oxychloride, with or without an additional solvent, to obtain the Intermediary of Formula A (Lv = Cl).

Scheme 4

<img file="CU20160149A7_D0014.tif" />

Scheme 4 illustrates a method for the preparation of compounds of Formula A wherein Y = N and X = CH. An aldehyde of Formula Cviii is treated with a

-61 alkylating agent, for example, 2-bromopropane (R¹ = isopropyl), and a base, such as K₂CO₃, in a suitable solvent, such as DMF or DMSO. The aldehyde of the Formula Cix is ​​then subjected to condensation of Knoevenagel with malonic acid, in general, in the presence of pyridine and piperldine, to obtain an acid of the Formula Cx. The acid can be converted into an acyl azide of the Formula Cxi by a variety of means known to the person of the medium level trade, for example, by sequential treatment with a chloroformate ester and then by reaction with sodium azide. After exposure to heat, the acyl azide can be subjected to a Curtius reaction to finally obtain a compound of the Formula Cxii. The Curtius reaction can be carried out in a suitable solvent, for example diphenyl ether, at a temperature generally greater than 200 ° C. The compound of the Formula Cxii is cyanized, using methods known to medium-level persons, such as treatment with zinc cyanide in palladium catalysts, to obtain a compound of the Formula Cxiii. It can be halogenated by methods known to medium-level persons, frequently, by treatment with phosphorus oxychloride, with or without an additional solvent, to obtain the intermediate of Formula A (Y = Ν, X = CH, Lv = Ci).

<img file="CU20160149A7_D0015.tif" />

Cxiv

Scheme 5

<img file="CU20160149A7_D0016.tif" />

<img file="CU20160149A7_D0017.tif" />

<img file="CU20160149A7_D0018.tif" />

<img file="CU20160149A7_D0019.tif" />

<img file="CU20160149A7_D0020.tif" />

TO

Scheme 5 illustrates a method for the preparation of compounds of Formula A, wherein X and Y = N. An ester of Formula Cxiv is nitrated with nitric acid to obtain a compound of Formula Cxv, which can then be reduced to an amine of the Formula Cxvi by methods known to the people of the medium level trade, for example, by treatment with tin chloride (ll) in acid solution. Subsequent treatment with formamide or similar reagents can be used to produce the formation of a quinazolinone of the Formula Cxvii. The resulting quinazolinone of the Formula Cxvii is cyanized, using methods known to the mid-level persons, such as treatment with zinc cyanide and a palladium catalyst, such as tetra (kis) triphenylphosphine palladium (0), in a solvent , such as THF, to obtain a nitric of the Formula Cxviii. It can be halogenated by methods known to medium-level persons, frequently, by treatment with phosphorus oxychloride, with or without an additional solvent, to obtain the intermediate of Formula A (Lv = Cl).

-63 Scheme 6

<img file="CU20160149A7_D0021.tif" />

Scheme 6 illustrates a method for the preparation of compounds of the Formula A. A nitrobenzoate ester of the Formula Cxix is ​​reduced by methods known to the people of the medium level trade, for example, by hydrogen in the presence of a palladium catalyst. in a solvent, such as ethanol, to an amine of the Formula Cxx. This amine is condensed with a derivative of malonic acid, such as Meldrum acid, in the presence of a trialkyl orthoformate, such as triethyl orthoformate, in a suitable solvent, such as ethanol, to obtain a compound of Formula Cxxi. Thermal cyclization is performed by heating a compound of the Formula Cxxi at a temperature, in general, greater than 200 ° C, and generally in a solvent, such as diphenyl ether or Dowtherm A, to obtain a quinolone of the Formula Cxxii, in some cases, accompanied by the regioisomer of the Formula Cxxiii. The separation of these isomers can be achieved by selective saponification with an alkali, for example, lithium hydroxide, in a solvent, such as aqueous THF, to obtain the desired quinolone of Formula Cxxiv. This compound can be halogenated by methods known to middle-level people, often by treatment with

-64 phosphorus toxicchloride with or without an additional solvent. Then, the carboxylic acid can be converted to carboxamide by methods known to the people of the medium level trade; for example, by treating with an excess of ammonia in a solvent compatible with the reaction, such as 1,4-dioxane, the intermediate of Formula A can be obtained.

Scheme 7

<img file="CU20160149A7_D0022.tif" />

Scheme 7 illustrates a method for the preparation of compounds of Formula A, wherein X and Y are both carbon. A naphthol of Formula Cxxv can be subjected to Fischer esterification to obtain a compound of Formula Cxxvi. The distal hydroxyl group can be masked using a suitable protecting group (PG), for example, by the formation of a silyl ether using standard conditions known by the people of the mid-level trade, for example, with t-butyldiphenylsilyl chloride and imidazole, in a suitable solvent, such as 1,2-dichloroethane, to obtain a compound of the Formula Cxxvii. Alkylation of the nearby hydroxyl group can be performed with an alcohol R¹-OH in the presence of triphenylphosphine and an azodicarboxylate ester ("Mitsunobu reaction") in a suitable solvent, such as THF, to obtain a compound of the Formula

-65Cxxviii, which can be saponified by an alkali to obtain a compound of the Formula Cxxix. Conversion into primary amide can be achieved using standard methods known to middle-level persons, for example, by conversion to an acyl chloride using a reagent, such as oxalyl chloride, to obtain a compound of the Formula Cxxx , which can be converted into the primary amide of Formula A, by methods known to the people of the middle level trade; for example, by exposure to an excess of ammonia, in general, in the presence of a suitable solvent, such as THF, water, or a mixture of solvents.

Scheme 8

<img file="CU20160149A7_D0023.tif" />

Scheme 8 illustrates a method for the preparation of additional compounds of Formula A. In this method, a compound of Formula A is misaligned to remove the alkyl group R¹ to obtain a compound of the Formula Ai. The misalignment can be carried out by standard methods known to middle-level persons, for example, by using anhydrous aluminum chloride or boron tribromide in a solvent, such as DCM, and can be performed more conveniently when R⁶ = CN The subsequent alkylation of the OH group can be done to install a new R group¹ to obtain a new compound of the Formula A, using methods known to the people of the medium level trade, for example, by treatment with an alcohol R¹-OH in the presence of triphenylphosphine and an azodicarboxylate ester ("Mitsunobu reaction") in a suitable solvent, such as THF, or by treatment with an alkylating agent, such as chloride, bromide or alkyl iodide (R¹-CI, R¹-Br or R¹-l), and a base, such as K₂CO₃, in a suitable solvent, such as THF or DMF.

-66 Scheme 9

<img file="CU20160149A7_D0024.tif" />

<img file="CU20160149A7_D0025.tif" />

<img file="CU20160149A7_D0026.tif" />

HO Scheme 9 illustrates a method for the preparation of certain compounds of Formula B of type R²-OH as used in Schemes 1 and 2. Compounds of the Formula Cxxxi are known in the chemical literature, in particular, those compounds wherein R_to and R_b they are both methyl and in which R_to is phenyl (substituted) and R_b en H. In this method, the compound of the Formula Cxxxi is treated with a suitable base, frequently, lithium hexamethyldisilazide or lithium diisopropylamide, in a suitable solvent, such as THF, ether, MTBE or 2-methylTHF, using known conditions in the chemical literature. Then, the mixture can be treated with an electrophile to install the electrophile Et in the lactam ring. Suitable electrophiles are known to medium-level persons and include, among others, halogenating agents, such as electrophilic halogenation species, alkylating agents, such as alkyl halides, carbonyl compounds, such as aldehydes, ketones or esters. , oxidizing agents, such as molecular oxygen or sulfonylloxazidines, amination agents, such as sulfonyl azides and sulfur-containing electrophiles, such as disulfides, thiocyanates, sulphonates and sulphonyl halides. The resulting substituted lactam of Formula Cxxxii can be subjected to this process a second time to install another electrophile in the lactam ring, indicated in the scheme as E₂. A person of the medium level trade may recognize that the electrophiles E-ι and E₂ they can undergo additional chemical transformations. It will also be recognized that the introduction of electrophiles E₄ and E₂ it can generate a mixture of stereoisomers, which can be separated by known methods in differentiated stereoisomerically pure compounds. Finally, treatment with an acid is often used to remove the aminal protecting group that contains R_to and R_b to obtain compound R₂OH of Formula B. It may also be recognized that electrophiles Ei and E₂they will finally produce the R substituents⁴ in the compound of Formula la.

-67 Scheme 10

ΕΥ O.

OR

<img file="CU20160149A7_D0027.tif" />

Cxxxi

<img file="CU20160149A7_D0028.tif" />

<img file="CU20160149A7_D0029.tif" />

Cxxxvii B

Scheme 10 illustrates a method for the preparation of certain compounds of type R²-OH as used in Schemes 1 and 2. In this method, the compound of Formula Cxxxi is oxidized to the olefin compound of Formula Cxxxiv using methods known in the chemical literature. Frequently, this is achieved by the removal reaction of a sulfoxide or selenoxide or the treatment can be carried out with a suitable base, such as lithium diisopropylamide and cyiorotrimethylsilane, and the subsequent oxidation of the resulting silyl ketene terminal with a palladium salt. and an allyl alcohol carbonate ester, in a transformation known to a middle-level person as the oxidation of Saegusa Tsuji. The olefin of the Formula Cxxxiv can be converted into a compound of the Formula Cxxxv using methods known in the chemical literature, frequently, by treatment with an organometallic reagent, such as methyl lithium (R_c = methyl) or ethylmagnesium chloride (R_c = ethyl), in the presence of ciorotrimethylsilane and a copper compound. Then, the compound of Formula Cxxxv can be treated with an electrophile, indicated in Scheme 10 as E_1: to install the electrophile Ei in the lactam ring as previously described in Scheme 9. Similarly, the resulting compound of Formula Cxxxvi can be subjected to this procedure a second time to install another electrophile in the lactam ring, indicated in Scheme 10 as E₂. A person of the medium level trade may recognize that the electrophiles E₁ and E₂ and the group R_c they can undergo additional chemical transformations. It may also be recognized that the

-68 Introduction of Group R_c and the electrophiles Εί and E₂ It can generate a mixture of stereoisomers, which can be separated into differentiated stereoisomerically pure compounds. As in Scheme 9, treatment with an acid is often used to remove the aminal protecting group containing R_to and R_b to obtain compound R²-OH of Formula B. It may also be recognized that group R_c and the electrophiles E-ι and E₂ they will finally produce the R substituents⁴ in the compound of Formula la.

OR

<img file="CU20160149A7_D0030.tif" />

Cxxxiv

Scheme 11

<img file="CU20160149A7_D0031.tif" />

<img file="CU20160149A7_D0032.tif" />

Scheme 11 illustrates a method for the preparation of certain compounds of type R²-OH as used in Schemes 1 and 2. In this method, the olefin compound of Formula Cxxxiv is subjected to cyclopropagation by methods known in the chemical literature, frequently, by treatment with a suitably substituted sulfonium salt and a adequate base. A person of the medium level trade may recognize that the Rd and Re groups may undergo additional chemical transformations. It will also be recognized that the introduction of the cyclopropane ring containing the Rd and Re groups can generate a mixture of stereoisomers, which can be separated by known methods in differentiated pure stereoisomerically compounds. As in Scheme 9, treatment with an acid is often used to remove the aminal protecting group containing Ra and Rb to obtain compound R²-OH of Formula B. It may also be recognized that the cyclopropane ring containing the groups Rd and R_and will eventually produce the R substituents⁴ in the compound of Formula la.

-69 Scheme 12

<img file="CU20160149A7_D0033.tif" />

Cxli Cxlii B

Scheme 12 illustrates a method for the preparation of certain compounds of type R²-OH as used in Schemes 1 and 2. In this method, the olefin of Formula Cxxxix, which has PGt and PG protecting groups₂ suitable, where PG₄it is, for example, a carbamate, such as t-butyl carbamate and PG₂, for example, is a trialkylsilyl, such as TBDMS, can be converted into a compound of the Formula Cxl by methods known in the chemical literature. Frequently, this is achieved by treatment with an organometallic reagent, such as methyl lithium (R_c= methyl) or ethylmagnesium chloride (R_c = ethyl), in the presence of chlorotrlmethylsilane and a copper compound. Then, the compound of Formula Cxl can be treated with an electrophile (E ^ to install the electrophile E-ι in the lactam ring as previously described in Scheme 9. Similarly, the resulting compound of Formula Cxli is You can submit this procedure a second time to install another electrophile (E₂). A person of the medium level trade may recognize that electrophiles E₄ and E₂ and the group R_c they can undergo additional chemical transformations. It may also be recognized that the introduction of group R_c and the electrophiles Ei and E₂ It can generate a mixture of stereoisomers, which can be separated into differentiated stereoisomerically pure compounds. As in Scheme 9, treatment with an acid is often used to remove the aminal protecting group containing R_to and Rb to obtain compound R²-OH of the

-70 Formula B, It may also be recognized that group R_c and the electrophiles Ei and E₂they will finally produce the R substituents⁴ in the compound of Formula la.

Scheme 13

<img file="CU20160149A7_D0034.tif" />

Scheme 13 illustrates a method for the preparation of certain compounds of type R²-OH as used in Schemes 1 and 2. In this method, the compound of the Formula Cxxxi is treated with a suitable base, and then with an electrophile (Ef to Install the electrophile E1 in the lactam ring, as described previously in Scheme 9. The compound of Formula Cxliii is oxidized to an olefin compound of Formula Cxliv by methods known in the chemical literature, as previously described in Scheme 10. The olefin compound of the Formula Cxliv is subjected to cyclopropagation, as previously described in Scheme 11. A person of the medium level trade may recognize that groups Ei, Rd and Re may undergo additional chemical transformations. It will also be recognized that the introduction of the cyclopropane ring containing the En Rd and Re groups can generate a mixture of stereoisomers, which can be separated by known methods in differentiated stereoisomerically pure compounds. As in Scheme 9, treatment with an acid is often used to remove the aminal protecting group containing Ra and Rb to obtain compound R²-OH of Formula B. It may also be recognized that the cyclopropane ring containing the groups Ευ R_d and R_and will eventually produce the R substituents⁴ in the compound of Formula la.

-71 Scheme 14

<img file="CU20160149A7_D0035.tif" />

<img file="CU20160149A7_D0036.tif" />

<img file="CU20160149A7_D0037.tif" />

Scheme 14 illustrates a method for the preparation of certain compounds of type R²-OH as used in Schemes 1 and 2. In this method, the olefin compound of Formula Cxxxi is converted to a compound of Formula Cxxxv by methods known in the chemical literature, as previously described in Scheme 10. The compound of Formula Cxxxv is oxidized to an olefin compound of Formula Cxlvi by methods known in the chemical literature, as previously described in Scheme 10. The olefin compound of the Formula Cxxxv is subjected to cyclopropagation, as previously described in Scheme 11. A person of the medium level trade may recognize that the Rc, Rd and Re groups may undergo further chemical transformations. It will also be recognized that the introduction of the cyclopropane ring containing the groups Rc, Rd and Re can generate a mixture of stereoisomers, which can be separated by known methods in differentiated stereoisomerically pure compounds. As in Scheme 9, treatment with an acid is often used to remove the aminal protecting group containing Ra and Rb to obtain compound R²-OH of Formula B. It may also be recognized that the cyclopropane ring containing the groups Rc, R_d and R_and will eventually produce the R substituents⁴ in the compound of Formula la.

-72 Scheme 15

<img file="CU20160149A7_D0038.tif" />

<img file="CU20160149A7_D0039.tif" />

<img file="CU20160149A7_D0040.tif" />

Scheme 15 illustrates a method for the preparation of certain compounds of type R²-OH as used in Schemes 1 and 2. In this method, the olefin of the Formula Cxxxi can be converted into a compound of the Formula Cxlviii by methods known in the chemical literature, frequently, by treatment with an olefin reagent , such as ethylene or propylene, by irradiation with ultraviolet light in a suitable solvent, such as acetone. A person of the medium level trade may recognize that the Rf, Rg, Rh and R¡ groups can undergo additional chemical transformations. It will also be recognized that the introduction of the cyclobutane ring containing the groups Rf, Rg, Rh and R¡ can generate a mixture of stereoisomers, which can be separated by known methods in differentiated stereoisomerically pure compounds. As in Scheme 9, treatment with an acid is often used to remove the aminal protecting group containing Ra and Rb to obtain compound R²-OH of Formula B. It may also be recognized that the cyclobutane ring containing the groups Rf, R_g, R_h and R¡ will finally produce the R substituents⁴ in the compound of Formula la.

Experimental procedures and working examples The synthesis of various compounds of the present invention is illustrated below. Other compounds within the scope of the present invention can be prepared by the methods illustrated in these examples, either alone or in combination with techniques generally known in the art.

It will be understood that the intermediary compounds of the aforementioned invention are not limited to the particular enantiomer indicated, but include

-73 all stereoisomers and mixtures thereof. It will also be understood that compounds of the Formula may include intermediates of compounds of the Formula la.

-74 Experimental procedures

In general, the experiments are carried out in an inert atmosphere (nitrogen or argon), in particular, in those cases where they are used Intermediate or reagents sensitive to oxygen or moisture. Commercial solvents and reagents are generally used without further purification, including anhydrous solvents where applicable (generally, Sure-Seal ™ products from Aldrich Chemical Company, Mllwaukee, Wisconsin). In general, the products were dried under vacuum before being used in other reactions or subjected to biological tests. Mass spectrometry data are reported from Instruments of liquid chromatography mass spectrometry (LCMS), chemical ionization at atmospheric pressure (APCI) or gas chromatography-mass spectrometry (GCMS). The chemical shifts of nuclear magnetic resonance (NMR) data are expressed in parts per million (ppm, δ), with reference to the residual peaks of deuterated solvents that were used.

For the procedures that refer to synthesis in other examples or methods, the reaction conditions (reaction duration and temperature) may vary. In general, after the reactions, thin layer chromatography and / or liquid chromatography-mass spectrometry are performed and undergo preparation where appropriate. A person of the medium level trade may recognize that the purifications may vary according to the experiments: in general, sorbents, solvents and the proportions of solvents used for eluents / graders are chosen to obtain R_F or adequate retention times. A person of the mid-level trade will also recognize that HPLC purifications can be performed in various ways, including the use of normal stationary phases, reverse stationary phases, chiral stationary phases and supercritical eluents. The appropriate options of conditions for purifications by chromatography and HPLC will be differentiated by a person of the medium level trade.

The following preparations describe the preparation of certain intermediates used in the methods and examples below. The following preparations, methods and examples are intended to illustrate particular embodiments of the Invention and its preparations and are intended to limit the memory

-75 descriptive or claims in any way. Unless otherwise indicated, all reagents were obtained commercially.

Unless otherwise indicated, the following abbreviations have the meanings indicated below:

APCI - chemical ionization at atmospheric pressure br. - wide peaks ° C - degrees Celsius

CDCI₃ - deuterated chloroform

CD3OD- deuterated methanol d - doublet peak dd - double doublet peak

D₂O - deuterium oxide dmso-d₆ - perdeuterated dimethyl sulfoxide dt - double triplet peak g-gram (s)

H (for example, 1 H, 2 H) - hydrogen (s) hr - hour (s)

LC - liquid chromatography m - multiplet M - molarity mg - gram (s)

MHz - megahertz min - minute (s) ml - milliliter (s) mmol - millimol (s) mp - melting point

MS - mass spectrum

NMR / NMR - nuclear magnetic resonance pH - negative logarithm of hydronium ion concentration psi - pounds per square inch q - peak of the quartet s - peak of the singlet t - peak of the triplet

-76td - double triplet peak pl - microliter

Unless otherwise indicated, the following chemical formulas and acronyms have the following meanings:

AcOH - glacial acetic acid BF₃-Et₂O - boron trifluoro etherate BHT - 2,6-dit-t-butyl-4-metiIphenol CHCI₃ - chloroform

DAST - sulfur (diethylamino) trifluoride

DCM - dichloromethane

DMAP - (4-dimethylamino) pyridine

DMF - dimethylformamide

DMSO - dimethylsulfoxide

EDCI - N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride

Et₃N - triethylamine

EtOAc - ethyl acetate

EtOH - ethanol

HCI - hydrochloric acid

HNO₃ - nitric acid

H₂SW₄ - sulfuric acid

H₃PO₄ - phosphoric acid

LDA - lithium diisopropylamide

MeCN - acetonitrile

MeOH - methanol

MgSO₄ - anhydrous magnesium sulfate

K₂CO₃ - Potassium carbonate

K₃PO₄ - anhydrous tribasic potassium phosphate

KOH - potassium hydroxide

MTBE - methyl t-butyl ether

Na₂CO₃ - sodium carbonate

Na₂SW₄ - anhydrous sodium sulfate

NaBH₄ - sodium borohydride

NaHCO₃ - sodium bicarbonate

-77NaOH - sodium hydroxide

NFSI - N-fluoro (bisbenzenesulfonyl) imide, CAS 133745-75-2

NH4CI - Ammonium Chloride

POCI3 - phosphorus oxychloride

TFA - trifluoroacetic acid

THF - tetrahydrofuran

TMSCI - chlorotrimethylsilane

-78 PREPARATIONS

Preparation 1: 1-Chloro-7-methoxyisoquinone-6-carbonyl (Pl)

Step 1. Synthesis of methyl 4-iodo-3-methoxybenzoate (CAS 35387-92-9, C1),

To a solution of 3-hydroxy-4-iodobenzoic acid (CAS 58123-77-6, C12) (10800 g,

40.9 moles) in DMF (65 I) K was added₂CO₃ (25398 g, 184 mol), and then dimethyl sulfate (11352 g, 90 mol) was added slowly. This mixture was heated at about 50 ° C overnight. The reaction mixture was cooled to about 25 C, diluted with EtOAc (50 I) and filtered through a plug of Celite®. The solid was washed carefully with EtOAc (10 IX 3). The combined EtOAc filtrates were poured into water. After stirring for about 30 min, the EtOAc layer was separated and also washed sequentially with water, 1 M NaOH and brine. The EtOAc layer was separated, dried over Na₂SO4, filtered and concentrated to obtain the title compound C1. Yield: 11750 g (98%).

Stage 2. Synthesis of (4-iodo-3-methoxyphenyl) methanol (CAS 244257-61-2, C2),

To a solution of compound C1 (11750 g, 40.2 mol) in THF (35 I) was added NaBH₄ (7645 g, 201.09 moles) and was refluxed. While refluxing, MeOH (25 I) was slowly added to the reaction mixture at a rate of about 1 I per hour. After the reaction was completed, it was poured into a dilute cold HCI solution. Once the excess of NaBH₄ was quenched, the solution was filtered and extracted with EtOAc (2.5 IX 3). The combined EtOAc extracts were washed sequentially with water, brine and dried over Na₂SW₄. The solvent was evaporated under reduced pressure, and the resulting crude material was treated with MTBE. The resulting solid was filtered, and the filtrate was washed with water, brine, dried over Na₂SW₄ and leaked. The solvent was evaporated under reduced pressure to obtain the title compound C2. Yield: 9900 g (93%).

Stage 3. Synthesis of 4-iodo-3-methoxybenzaldehyde (CAS 121404-83-9, C3).

To a solution of compound C2 (9900 g, 34.5 mol) in CHCI₃ (186 I), manganese dioxide (18000 g, 207 moles) was added, and the resulting mixture was refluxed for about 16 h. The mixture was cooled to about 25 ° C and filtered through a pad of Celite, which was then carefully washed with CHCI₃. The CHCI₃ It was evaporated under reduced pressure to obtain the title compound C3.

-79 Yield: 9330 g (95%). ¹H NMR (400 MHz, CDCI₃): δ 9.95 (s, 1 H), 7.99 (d, 1 H),

7.14 (dd, 1 H), 3.95 (s, 3 H).

Step 3. Synthesis of 6-iodo-7-methoxyisoquinoline (CAS 244257-63-4, C4).

To a solution of compound C3 (9300 g, 35 mol) in toluene (60 I) was added amino acetaldehyde dimethyl acetal (5590 g, 53 mol), and the mixture was refluxed for about 4 h, while the water released by a Dean - Stark water collector. The reaction mixture was cooled to about 0 ° C, then trifluoroacetic anhydride (22305 g, 106 moles) was added, and then BF₃-Et₂O (15080 g, 106 moles), and the internal temperature was maintained below 5 ° C. The reaction mixture was stirred at about 25 ° C for about 16 h and was quenched by pouring it into a mixture of ice and ammonium hydroxide. The product was extracted with EtOAc (10 1X3), and the combined EtOAc extracts were washed sequentially with water and brine. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated to obtain a dark tan residue. It was treated with a mixture of MTBE and hexane (1: 1 v / v, 30 I), and then with 6 M HCI (9 I), with stirring. The precipitated solid was filtered and washed with MTBE. The solid was suspended in EtOAc (5 I) and made alkaline with ammonium hydroxide. The EtOAc layer was separated, washed with brine, dried over Na₂SW₄, filtered and concentrated to obtain the crude compound C4 as a brown solid. HPLC (230 nm) showed that it had a purity of about 83%.

The crude material (1000 g) was absorbed in AcOH (2.5 I) and stirred for about 90 min at about 25 ° C. The solid was filtered and washed with AcOH (500 ml). The filtrate was neutralized with saturated aqueous Na solution.₂CO₃. The resulting precipitated solid was filtered, washed with water (4 I) and dried in the oven at about 70-75 ° C for about 5 h to obtain about 780 g of pure C4. Similarly, the remaining crude C4 (4 kg) was purified to obtain the title compound C4. Yield: 4300 g (42%).¹H NMR (400 MHz, CDCI₃): δ 9.15 (s, 1 H), 8.45 (d, 1 H), 8.35 (s, 1 H),

7.45 (d, 1 H), 7.15 (s, 1 H) 4.00 (s, 3 H).

Step 4. Synthesis of 7-methoxysoquinol-6-carbonitrile (C5).

To a solution of compound C4 (4300 g, 15 mol) in DMSO (39 I) was added copper cyanide (l) (2954 g, 33 mol), and the mixture was heated at about 120 ° C for about 3 h. The reaction mixture was activated by pouring it into a mixture of ice and ammonium hydroxide (40 I) and filtered. The filtrate was extracted with EtOAc (10 IX

-802). While stirring, the solid residue was re-treated with ammonium hydroxide solution (10 I) and EtOAc (10 I). After filtration, the precipitated material was washed repeatedly with a mixture of MeOH and CHCI₃ (1: 9, v / v) several times, and the combined extracts were washed with brine. The extracts were dried in Na₂SW₄, filtered and concentrated under reduced pressure. The resulting crude material was triturated with hexane to obtain the title compound C5. Yield: 2250 g (87%).¹H NMR (400 MHz, CDCI₃): δ 9.25 (br. s, 1 H), 8.55 (br. s, 1 H), 8.15 (s, 1 H), 7.60 (d, 1 H), 7.30 (s, 1 H), 4.05 (s , 3 H).

Step 5. Synthesis of N-oxide of 7-methoxyisoquinolin-6-carbonyl (C6).

To a solution of compound C5 (500 g, 2.7 moles) in DCM (5 I), 30% peracetic acid (413 g, 5.4 moles, 2 equivalents) was slowly added at about 40-45 ° C during around 4 h. The resulting mixture was stirred at the same temperature for about 16 h. At this stage, 50% of the starting material had been consumed, and for the additional conversion another 2 equivalents of peracetic acid were added. The reaction mixture was heated to about 40-45 ° C and monitored by TLC. After approximately 8 h more, there were still traces of the starting material. An additional 0.5 equivalent of peracetic acid was added, and the reaction continued for about 5 h. The heterogeneous reaction mass was cooled to about 25 ° C and filtered. The resulting solid was washed with water (2 IX 3) and then triturated with acetone (2 I). At the time of drying, 250 g of compound C6 were obtained.

The DCM layer resulting from the filtration was washed with saturated aqueous NaHCO solution.₃ (15 I). The resulting aqueous layer was reextracted with DCM (1.5 IX 2), and the combined layers of DCM were washed with brine. At the time of concentration, 150 g of compound C6 were obtained.

The acidic water layer of the original filtrate was made alkaline with saturated aqueous Na solution.₂CO₃ (5 I) and extracted with DCM (1 IX 2). The DCM layer was dried in Na₂SW₄, filtered and concentrated to obtain 30 g of compound C6. The batches of compound C6 were combined to obtain the title compound C6. Yield: 430 g (80%).¹H NMR (400 MHz, CDCI₃): δ 8.85 (br. s „1 H), 8.05 - 8.18 (m, 2 H), 7.71 (d, 1 H), 7.12 (s, 1 H), 4.08 (s, 3 H).

Step 5. Synthesis of 1-chloro-7-methoxisoisoolin-6-carbonitrile (P1).

-81A a suspension of compound C6 (700 g, 3.5 moles) in DCM (14 I) was added dropwise phosphoryl chloride (333.5 mL, 3.5 moles) for about 1 h. After the addition was completed, the reaction mixture was a homogeneous solution and stirred at about 25 ° C overnight. After the reaction was completed, the mixture was poured into ice water (5 I), and the resulting solid was filtered. The solid was washed with saturated aqueous NaHCO solution.₃ (1 IX 2) and then with water. At the time of drying, 360 g of compound P1 were obtained with a purity of 93% according to HPLC.

The DCM layer resulting from the filtration was separated. The aqueous layer resulting from the filtration was extracted with DCM (1 IX 2). The combined DCM solutions were washed with saturated aqueous NaHCO solution.₃ and then sequentially with water and brine. The DCM solution was dried in Na₂SW₄, was filtered and concentrated to obtain 300 g of compound P1 with a purity of 75% according to HPLC. The material was absorbed in a mixture of AcOH (900 ml) and EtOAe (1200 ml), then heated at about 70-75 ° C for about 30 min. The solid was filtered while the mixture was hot (about 70 ° C). The solid was also washed with EtOAe (300 ml), then with hexane (350 ml) and dried to obtain 200 g of compound P1 with a purity of 95% according to HPLC.

P1 with a purity of 93% according to HPLC (360 g, 93%) was further purified by triturating it with a mixture of EtOAe and MTBE (1: 1, v / v) and filtered. At the time of drying, 300 g of compound P1 were recovered. The batches of P1 were combined to obtain the title compound P1. Yield: 500 g (65%).¹H NMR (400 MHz, CDCIs): δ 8.30 (d, 1 H), 8.18 (s, 1 H), 7.65 (s, 1 H), 7.58 (d, 1 H), 7.15 (s, 3 H).

Preparation 2: 1-Chloro-7-Sopropoxyisoquinolin-6-Carbonitrlo (P2)

<img file="CU20160149A7_D0041.tif" />

Stage 1. Synthesis of 3-bromo-4-isopropoxybenzaldehyde (CAS 191602-84-3, C7),

A mixture of 3-bromo-4-hydroxybenzaldehyde (1500 g, 7.5 mol) and K₂CO₃ (1290 g, 9.3 mol) in anhydrous DMSO (15 I) was treated with 2-bromopropane (1010 g, 8.2 mol) and stirred at about 55 ° C overnight. 200 g (1.6 mol) of additional 2-bromopropane were added, and the reaction continued for approximately 4 h more.

-82 The reaction was cooled to about 30 ° C, and EtOAc (22.5 I) and water (22.5 I) were added. The EtOAc phase was separated, and the aqueous phase was reextracted with EtOAc (2 X 7.5 I). The combined EtOAc phases were washed with water (2x15 I), then with brine (15 I), dried over Na₂SW₄, filtered and concentrated to obtain the title compound C7. Performance; 1800 g (99%).¹H NMR (400 MHz, CDCI₃) δ 9.82 (s, 1 H), 8.07 - 8.08 (d, 1 H), 7.76 - 7.79 (d, 1 H), 6.98 (d, 1 H), 4.67 - 4.74 (m, 1 H), 1.42 - 1.44 (d, 6 H).

Step 2. Synthesis of acid (E) -3- (3-bromo-4-sopropox¡fenll) acrylic (CAS 1344851-826, C8).

Compound C7 (1800 g, 7.4 mol) in anhydrous pyridine (7.56 I) was treated with malonic acid (1002 g, 9.6 mmol) and piperidine (316 g, 3.7 mmol) and heated to reflux for about 2 h. The solvent was removed by distillation under reduced pressure. It was treated with cold water (37.8 I) and stirred for about 0.5 h, then acidified to adjust the pH to about 4.0 with AcOH (about 300 ml). The suspension was vigorously stirred for about 1 hour to disintegrate all solids, and then the product was collected by filtration, washed with water (3.6 I) and dried in vacuo to obtain the title compound C8. Performance; 2014 g (95%).¹H NMR (400 MHz, dmso-d₆) δ 7.94 - 7.95 (d, 1 H) 7.64 - 7.67 (dd, 1 H), 7.48 - 7.52 (d, 1 H), 7.14-7.16 (d, 1 H), 6.43 - 6.47 (d, 1 H) , 4.71 -4.77 (m, 1 H), 1.29-1.31 (d, 6 H). Step 3. Synthesis of azide of (E) -3- (3-bromo-4-isopropoxlfenyl) acryloyl (C9),

To a stirred solution of compound C8 (1000 g, 3.5 mol) in acetone (17.5 I), Et was added₃N (355 g, 3.5 mol), and the mixture was cooled to about -5 ° C. Ethyl chloroformate (495 g, 4.56 mol) was added dropwise while maintaining the temperature at about -5 ° C. After the addition was complete, the mixture was stirred for about 1 h more at about -5 ° C. A solution of sodium azide (342 g, 5.3 mol) in water (1264 ml) was added slowly at about -5 ° C. After the addition of sodium azide solution was completed, the reaction mixture was slowly heated to about 25 ° C and stirred for about 0.5 h. The reaction mass was quenched by the addition of water (50 I) and stirred for about 30 minutes at about 25 ° C. The precipitate was filtered, washed with water (2 I) and dried to obtain the title compound C9. Yield: 978 g (90%).¹H NMR (300 MHz, dmso-d₆) δ 8.07 - 8.08 (d, 1 H), 7.74 - 7.77 (dd, 1 H), 7.60 (s, 1 H),

7.16-7.20 (d, 1 H), 6.60-6.66 (d, 1 H), 4.74-4.82 (m, 1 H), 1.29-1.32 (d, 6 H).

-83 Stage 4. Synthesis of 6-Bromo-7-Sopropoxyisoquinolin-1 (2H) -one (CIO).

To a mixture of diphenyl ether (8 I) and tri n-butylamine (328 g, 1.77 mol) preheated to about 230 ° C, compound C9 (550 g, 1.77 mol) dissolved in diphenyl ether (2, 5 I) while the temperature was maintained at around 230 ° C. After the addition was completed, stirring and heating continued for about 0.5 h. The reaction mixture was cooled to about 25 ° C, and slowly added to hexane (27.5 I). The resulting suspension was cooled to about 0 ° C and stirred for about 0.5 h. The crude precipitate was filtered; The precipitate was washed with cold hexane (5.5 I). The wet cake was dried under vacuum to obtain 310 g of crude C10. This reaction was repeated three more times to obtain 1064 g of crude C10. It was dissolved in THF (5.3 I) under reflux and cooled to about 0 ° C. The suspension was stirred for about 0.5 h, then filtered, and the filter cake dried under vacuum to obtain 574 g of C10. The filtrate was concentrated and purified by chromatography to obtain an additional 181 g to obtain the title compound C10. Yield: 755 g (46%).¹H NMR (300 MHz, CDCI₃) δ 8.24 - 8.26 (d, 1 H), 8.16 (s, 1 H), 7.65 (s, 1 H), 7.55 7.56 (d, 1 H), 4.85 - 4.91 (m, 1 H), 1.51 - 1.52 (d, 6 H).

Step 5. Synthesis of 7-isopropox¡-1-oxo-1,2-d¡hydroisoquinolin-6-carbon¡trile (CU).

Compound C10 (490 g, 1.74 mol) and zinc cyanide (265 g, 2.25 mol) were added to dry DMF (9.8 I) and stirred well for about 5 min at 25 ° C. The reaction mixture was degassed with nitrogen for about 20 minutes, then tetra (kis) triphenylphosphine palladium (0) (120 g, 0.104 mol) was added, and the reaction mixture was stirred for about 5 min at about 25 ° C before heating to around 100 ° C. The mixture was maintained for about 16 hours at about 100 ° C. The reaction mixture was cooled to about 25 ° C, diluted with EtOAc (4.9 I) and stirred for about 0.5 h. The mixture was filtered through celite, which was washed with EtOAc (1 I). The combined filtrate was concentrated at a pressure of about 10 torr to about 75 ° C. Water (4.9 I) was added to the residue, and the mixture was stirred for about 0.5 h. The precipitate was filtered, washed with water (1 I) and dried in vacuo at about 60 ° C. The precipitate was stirred for about 0.5 h with MTBE (4.9 I) and filtered. This process was repeated two more times, then the filter cake was washed with MTBE (0.5 I) and dried in vacuo at about 60 ° C to obtain the title compound C11. Yield: 390 g (98%)¹H NMR (400 MHz, CDCI₃) δ

-848.24 - 8.26 (d, 1 Η), 8.16 (s, 1 Η), 7.65 (s, 1 Η), 7.54 - 7.56 (d, 1 Η), 4.85 - 4.99 (m, 1 Η), 1.51 - 1.52 (d, 6 Η).

Stage 6, Synthesis of 1-Chloro-7-Sopropox¡soqu¡nol¡n-6-carbonitr¡lo (P2).

Compound C11 (390 g, 1.7 mol) and POCI₃ (10.97 kg, 71.5 mol) were stirred for about 5 min at about 25 ° C, then heated to about 100 ° C and kept at around 100 ° C for about 0.5 h . The reaction mixture was cooled to about 25 ° C and concentrated under reduced pressure to about 60 ° C. The residue was quenched with ice (7.8 kg), then neutralized with a solution of K₂CO₃ 25% (7.8 I) and stirred until the mixture had a pH of about 7. The solution was extracted with DCM (3x5 I), and the combined extracts were washed with a NaHCO solution₃ 10% (2 x 3.9 l). The DCM separated, dried in Na₂SW₄, was filtered and concentrated. N-Heptane (3.9 I) was added to the residue, and the mixture was stirred for about 0.5 h at about 25 ° C. The precipitate was filtered, and the filter cake was washed with n-heptane (390 ml) and dried in vacuo at about 60 ° C to obtain the title compound P2. Yield: 338 g (80%)¹H NMR (300 MHz, dmso-de) δ 8.73 (s, 1 H), 8.29 - 8.31 (d, 1 H), 7.89 - 7.91 (d, 1 H), 7.67 (s, 1 H), 5.02 5.06 ( m, 1 H), 1.41 -1.43 (d, 6 H).

Preparation 3: 4-Chloro-6-methoxyquinazolin-7-carbonitrile (P3)

Stage 1, Synthesis of 3-hydroxy-4-iobenzoic acid (CAS 58123-77-6, C12).

To a stirred solution of 3-hydroxybenzoic acid (25 g, 181 mmol) in water (180 ml), 1 M aqueous NaOH (188 ml) and sodium iodide (28.1 g, 188 mmol) were added, then added slowly an aqueous solution of sodium hypochlorite (0.9 M, 209 mi). The mixture was stirred at about 25 ° C for about 2 h, then cooled on ice and acidified with concentrated HCI at pH = 3. A sufficient amount of 10% ascorbic acid solution was added to obtain a colorless mixture. . The remaining precipitate was filtered, washed with water and dissolved in EtOAc. The EtOAc solution was washed with brine, dried over Na₂SW₄, was filtered and concentrated to obtain the title compound C12. Yield: 34 g (71%)¹H NMR (400 MHz, dmso-d₆) δ

12.98 (brs, 1 H), 10.65 (s, 1 H), 7.78 (dd, 1 H), 7.32 (d, 1 H), 7.11 (dd, 1 H).

Step 2. Synthesis of methyl 4-iodo-3-methoxybenzoate (CAS 35387-92-9, C13).

To a stirred solution of compound C12 (84 g, 318 mmol) in DMF (300 ml) at about 0 ° C, K was added₂CO₃ (177 g, 1273 mmol) and then methyl iodide

-85 (79.3 mi, 1273 mmol). The mixture was stirred at about 25 ° C for about 16 h, then diluted with EtOAc (2 I) and washed with water (600 mL x 2) and then with brine (100 mL x 2). The EtOAc was dried in Na₂SW₄, filtered and concentrated to obtain the title compound C13. Performance; 84 g (90%)¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, 1 H), 7.44 (d, 1 H), 7.36 (dd, 1 H), 3.93 (s, 3 H), 3.91 (s, 3 H).

Step 3. Synthesis of methyl 4-iodo-5-methox-2-n -trobenzoate (C14).

A stirred solution of compound C13 (10 g, 38 mmol) in AcOH (92 mL) was treated with HNO.₃ 70% concentrated (11.9 ml) and cooled in a water bath at about 25 ° C, then acetic anhydride (46 ml) was added. Then, the mixture was placed in a preheated oil bath at about 70 ° C. After about 2 h, the reaction mixture was cooled to about 25 ° C, diluted with a solution of 1 M NaOH (200 mL) and extracted with EtOAc (200 mL x 2). The combined extracts were washed with NaHCO₃, brine, dried in Na₂SW₄, filtered and concentrated. The residue was purified by column chromatography to obtain the title compound C14. Yield: 10 g (78%)¹H NMR (400 MHz, dmso-d₆) δ 8.50 (s, 1 H),

7.32 (s, 1 H), 4.01 (s, 3 H), 3.84 (s, 3 H).

Step 4. Synthesis of methyl 2-amine-4-iodo-5-methoxybenzoate (C15).

To a stirred solution of compound C14 (19 g, 56 mmol) in MeOH (300 ml), a solution of stannous chloride dihydrate (40.7 g, 180 mmol) in 120 ml of 6 M HCl was added. The mixture was stirred. at about 25 ° C for about 16 h, then it was concentrated. The residue was stirred with a saturated aqueous solution of potassium fluoride and extracted twice with EtOAc. The combined extracts were dried in Na₂SW₄, filtered and concentrated. The residue was triturated with a mixture of DCM and hexane to obtain the title compound C15. Yield: 14 g (81%)¹H NMR (400 MHz, dmso-d₆) δ 7.35 (s, 1 H), 7.14 (s, 1 H), 3.79 (s, 3 H), 3.68 (s, 3 H).

Stage 5. Synthesis of 7-iodo-6-methoxyquinoline-4 (3H) -one (C16).

A stirred solution of compound C15 (17 g, 55 mmol) in formamide (170 ml) was heated at about 160 ° C for about 18 h. The reaction mixture was cooled to about 25 ° C, diluted with water (170 ml) and stirred at about 10 ° C for about 30 minutes. The precipitate was filtered, washed with water, then with diethyl ether and dried in vacuo to obtain the title compound C15. Yield: 12 g (71%)¹H NMR (400 MHz, dmso-d₆) δ 8.14 (s, 1 H), 7.99 (s, 1 H), 7.44 (s, 1 H), 7.16 (brs, 1 H), 3.93 (s, 3 H).

-86 Stage 6. Synthesis of 6-methoxy-4-oxo-3,4-dihydroquinoline-7-carbonitrile (C17).

A stirred solution of compound C16 (16 g, 53 mmol) in dimethylacetamide (80 ml) was degassed with argon for about 15 minutes, then zinc cyanide (6.22 g, 53 mmol) was added, then TMEDA (2, 38 ml, 16 mmol), tris (dibenzylidenacetone) dipaladium (0) (4.85 g, 5.3 mmol) and Xantphos (3.06 g, 5.3 mmol). The mixture was heated at about 80 ° C for about 5 h under argon, then cooled to about 25 ° C, diluted with diethyl ether (1 I) and filtered. The precipitate was dissolved in a mixture of MeOH and DCM (1/4, v / v) and filtered through Celite®. The filtrate was concentrated, and the residue was purified by column chromatography to obtain the title compound C17. Yield: 5.4 g (50%)¹H NMR (400 MHz, dmso-d₆) δ 12.47 (br. s, 1 H), 8.17 (s, 1 H), 8.09 (s, 1 H), 7.69 (s, 1 H), 4.02 (s, 3 H). Step 7. Synthesis of 4-chloro-6-methoxyquinozol-7-carbonyl (P3).

A mixture of compound C17 (10 g, 49.8 mmol) and POCI₃ (250 ml) was heated at about 100 ° C for about 16 h, then cooled to about 25 ° C and concentrated. The residue was diluted with EtOAc, and the ethyl acetate solution was washed with water, saturated aqueous NaHCO solution.₃, brine, dried in Na₂SW₄, was filtered and concentrated. The residue was purified by column chromatography to obtain the title compound P3. Yield: 2.8g (27%)¹H NMR (400 MHz, dmso-de) δ 9.11 (s, 1 H), 8.75 (s, 1 H), 7.66 (s, 1 H), 4.14 (s, 3 H).

Preparation 4: 4-Chloro-6-¡sopropox¡qu¡nolin-7-carboxam¡da (P4)

<img file="CU20160149A7_D0042.tif" />

Step 1. Synthesis of methyl 2-hydroxy-5-n -trobenzoate (C18).

Slowly added H₂SW₄ concentrated (150 ml) to a solution of 2-hydroxy5-nitrobenzoic acid (1000 g, 5.4 mol) in dry MeOH (5 I). After the addition was completed, the mixture was heated at reflux for about 24 h. After the reaction was completed, the mixture was filtered, and the precipitate was reserved. The filtrate was concentrated to obtain a solid residue. The residue and the previous precipitate were dissolved in EtOAc and washed with water twice. Then, the EtOAc was washed with

-87salmuera, dried up in Na₂SW₄, filtered and concentrated to obtain the title compound C18. Yield: 900 g (84%)¹H NMR (300 MHz, CDCI₃) δ 11.42 (s, 1 H), 8.80 - 8.79 (d, 1 H), 8.31 - 8.35 (dd, 1 H), 7.07 - 7.10 (d, 1 H), 4.04 (s, 3 H).

Step 2. Synthesis of methyl 2-sopropoxy-5-n -trobenzoate (C19).

Compound C18 (900 g, 4.56 mol), triphenylphosphine (1.33 kg, 5.02 mol) and 2-propanol (3.8 kg, 5.02 mol) were dissolved in dry THF (18 I) and They cooled to about 5 ° C. Diisopropyl azodicarboxylate (1.01 kg, 5.02 mol) was added, the reaction was heated to about 25 ° C and stirred overnight. The mixture was concentrated under reduced pressure, and the residue was treated with EtOAc (5 I). The remaining undissolved solids were removed by filtration, and the filtrate was evaporated. The residue was purified by column chromatography to obtain the title compound C19. Yield: 760 g (70%)¹H NMR (300 MHz, CDCI₃) δ 8.60 (d, 1 H), 8.29 - 8.34 (dd, 1 H), 7.01 (d, 1 H),

4.73-4.77 (m, 1 H), 3.90 (s, 3 H), 1.33 (d, 6 H).

Step 3. Synthesis of methyl 5-amino-2-sopropoxybenzoate (C20).

A solution of compound C19 (760 g, 3.17 mol) in EtOH (12 I) was treated with palladium on carbon (76 g), and this mixture was stirred for about 1 h at about 25 ° C under a hydrogen atmosphere at around 50 psig. After the reaction was completed, the mixture was filtered through celite, and the filter cake was washed with additional EtOH. The filtrate was evaporated to obtain the title compound C20. Yield: 600 g (60%).¹H NMR (400 MHz, dmso-d₆) δ 6.83 - 6.85 (d, 1 H), 6.76 6.79 (dd, 1 H), 4.31 - 4.37 (m, 1 H), 3.86 (s, 3 H), 2.80 - 3.60 (br. s, 2 H) , 1.29 - 1.31 (d, 6 H).

Step 4, Synthesis of 5 - (((2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene) methyl) amino) -2-methyl isopropoxybenzoate (C21),

A mixture of compound C20 (600 g, 2.88 mol), Meldrum acid (640 g, 3.44 mol) and triethyl orthoformate (560 g, 3.44 mol) in EtOH (7 I) was heated to reflux overnight. The mixture was cooled to about 20 ° C, and the resulting precipitate was collected by filtration to obtain the title compound C21. Yield: 620 g (60%)¹H NMR (300 MHz, CDCI₃) δ 11.07 - 11.17 (br. d, 1 H), 8.53 - 8.58 (d, 1 H), 7.69 - 7.70 (d, 1 H), 7.29 - 7.33 (dd, 1 H), 7.02 - 7.05 (d, 1 H), 4.55-462 (m, 1 H),

2.91 (s, 3 H), 1.75 (d, 6 H), 1.38-1.40 (d, 6 H).

Step 5. Synthesis of methyl 6-isopropoxy-4-oxo-1,4-d¡hydroquinolin-7-carboxylate (C22),

Compound C21 (20 g, 55 mmol) was added portionwise to preheated Dowtherm A (480 ml) at about 240 ° C. Heating and stirring at that temperature continued for approximately 5 more minutes after the addition was completed. The mixture was cooled to about 20 ° C and purified by column chromatography to obtain 6.2 g of a mixture of compound C22 and 6sopropoxy-4-oxo-1,4-dihydroquinoline-5- methyl carboxylate. This procedure was repeated 29 more times with the same scale to obtain a mixture of title compound C22 and methyl 6-isopropox-4-oxo-1,4-dihydroquinolin-5-carboxylate. Yield: 311 g (72%)¹H NMR (400 MHz, dmso-d₆) δ 11.90 (s, 2 H), 7.94 - 7.92 (d, 1 H), 7.87 - 7.86 (d, 1 H), 7.83 (s, 1 H), 7.62 - 7.54 (m, 3 H), 6.01 - 6.02 (d, 1 H),

5.93 - 5.91 (d, 1 H), 4.72 - 4.66 (m, 1 H), 4.62 -4.56 (m, 1 H), 3.85 (s, 3 H), 3.76 (s, 3 H), 1.29-1.31 ( d, 6H), 1.20-1.22 (d, 6 H).

Step 6. Synthesis of 6-isopropox¡-4-oxo-1,4-dihydroquinolin-7-carboxylic acid (C23),

The mixture of compound C22 and methyl 6-isopropox-4-oxo-1,4-dihydroquinolin-5-carboxylate (311 g, 1.19 mol) was added to THF (1.55 I) and water (1.55 I ). Lithium hydroxide monohydrate (199 g, 4760 mmol) was added, and the mixture was stirred at about 25 ° C overnight. The reaction mixture was diluted with water and extracted with EtOAc 4 times until methyl 6-isopropoxy-4-oxo-1,4-d-hydroquinol-5-carboxylate was absent in the aqueous phase. The aqueous layer was adjusted to about pH = 1 by the addition of 1M HCI and extracted with EtOAc twice. The combined EtOAc extracts were dried in Na₂SW_4l filtered and concentrated to obtain the title compound C23. Yield: 129 g (44%)¹H NMR (400 MHz, dmso-d₆) δ 11.6 - 13.0 (br. s, 1 H), 8.04 - 8.06 (d, 1 H), 7.84 (s, 1 H), 7.60 (s, 1 H),

6.20 - 6.22 (d, 1 H), 4.69 - 4.73 (m, 1 H), 1.30 - 1.32 (d, 6 H).

Step 7. Synthesis of 4-Chloro-6-Sopropoxquinolin-7-Carboxamide (P4),

A mixture of compound C23 (129 g, 520 mmol) and POCI₃ (2 I) was heated at reflux for about 6 h. The mixture was concentrated under reduced pressure to obtain a dark oil that was immediately treated with 10 I of saturated ammonia gas solution in dioxane at about 0 ° C. Then, the mixture was stirred at about 25 ° C overnight. The reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with DCM (1 I) and washed with water. The DCM extract was concentrated to obtain a solid residue that was purified by triturating it with diethyl ether to obtain the

-89composite of title P4. Yield: 55 g (40%)¹H NMR (300 MHz, dmso-d₆) δ 8.90 (s, 1 H), 8.71 - 8.72 (d, 1 H), 7.80 (br. s, 1 H), 7.50 (s, 1 H), 4.90 (m, 1 H), 1.47 (d, 6 H).

Preparation 5: 5-hydroxy-3-methoxy-2-naphthalam (P5)

Stage 1. Synthesis of methyl 3,5-dlhydrox¡-2-naphthoate (C24),

A solution of 3,5-dihydroxy-2-naphthoic acid (2.2 kg, 10.8 mol) in anhydrous MeOH (16 I) was cooled below 25 ° C, then thionyl chloride (2.56 was added kg, 21.5 mol) over a period of about 3 h. After the addition, the mixture was stirred at about 25 ° C overnight. An additional 500 g of thionyl chloride was added slowly, and the mixture was stirred for an additional 16 hours until the reaction was complete. The reaction mixture was concentrated to dryness, and the residue was absorbed in cold water. The resulting suspension was adjusted to about pH = 8 with NaHCO₃ aqueous. The precipitate was filtered, washed with water (0.5 I x 3) and dried in vacuo to obtain the title compound C24. Yield: 2.25 kg (96%)¹H NMR (400 MHz, dmso-d_B) δ 10.19 (s, 1 H), 10.18 (s, 1 H), 8.37 (s, 1 H), 7.49 (s, 1 H),

7.39-7.42 (d, 1 H), 7.14-7.18 (t, 1 H), 6.88-6.90 (d, 1 H), 3.95 (s, 3 H).

Step 2. Synthesis of 5 - ((tert-butyldiphen¡ls¡l¡l) ox¡) -3-hydroxyl-2-naphthoate (C25).

To a solution of compound C24 (500 g, 2.3 mol) in 1,2-dichloroethane (7.5 I), imidazole (233 g, 3.4 mol) was added. After the addition, the mixture was heated to about 45 ° C and stirred for about 45 minutes before t-butyldiphellsilyl chloride (453 g, 2.7 mol) was added dropwise. Then, the mixture was heated to about 65 ° C and maintained at that temperature for about 2 hours. Water (3 I) was added to the mixture, and the dichloroethane layer was separated. The aqueous phase was extracted with DCM (1 I x 2). The combined DCM extracts were washed with water (2 x 2) and brine, dried over Na₂SW₄, filtered and concentrated under reduced pressure. Cold MeOH was added to the residue and stirred for about 10 minutes. The precipitate was filtered, washed with cold MeOH and dried under vacuum to obtain the title compound C25. Performance; 900 g (86%) This procedure was repeated to prepare additional compound C25.¹H NMR (300 MHz, dmso-d₆) δ 10.35 (s, 1 H),

8.42 (s, 1 H), 7.77 (s, 1 H), 7.69 - 7.72 (t, 4 H), 7.52 (m, 7 H), 6.90 - 6.96 (t, 1 H), 6.37 6.41 (d, 1 H), 3.97 (s, 3 H), 1.13 (s, 9 H).

Step 3. Synthesis of methyl 5 - ((tert-butyldiphen¡ls¡l) ox¡) -3-methoxy-2-naphthoate (C26).

-90 Triphenylphosphine (1.15 kg, 4.4 mol) was dissolved in THF (13 I) and treated with diisopropylazodicarboxylate (885 g, 4.4 mol), stirred and cooled to keep the temperature below about 25 ° C After the addition was complete, the mixture was stirred for about 10 minutes. Then, methanol (876 ml, 21.9 mol) was added to the mixture over a period of about 1 h and cooled to maintain the temperature approximately below 25 ° C. Compound C25 (1.0 kg, 2.2 mol) was added to the portion mixture. The resulting solution was heated at about 80 ° C for about 1 h. Then, the mixture was cooled to about 25 ° C and concentrated to dryness. The residue was purified by column chromatography, then heated to reflux with a 3/1 mixture of EtOH and petroleum ether for about 1 h to obtain the title compound C26. Performance; 500 g (49%) This procedure was repeated to prepare additional compound C26.¹H NMR (300 MHz, dmso-d₆) δ 8.24 (s, 1 H), 7.61 - 7.77 (m, 5 H), 7.42 7.52 (m, 7 H), 7.01 - 7.06 (t, 1 H), 6.50 - 6.53 (d, 1 H), 3.97 (s, 3 H), 3.86 (s, 3 H), 1.13 (s, 9 H).

Step 4, Synthesis of 5-hydroxy-3-methoxy-2-naphthoic acid (C27).

Compound C26 (1.33 kg, 2.8 mol) and lithium hydroxide monohydrate (475 g, 11.3 mol) were added to a mixture of THF (3 I), MeOH (500 ml) and water (3 I) . The mixture was stirred at about 25 ° C overnight, then the mixture was diluted with EtOAc (4 I) and water (2 I). The aqueous phase was separated, and the EtOAc phase was extracted with water (2 x 2). The combined aqueous phases were extracted with EtOAc (2 x 2), and then acidified at about pH = 3 with concentrated HCI. The precipitate was filtered, washed with water (1 x 3) and dried in vacuo to obtain the title compound C27. Yield: 533 g (86%).

This procedure was repeated to prepare additional compound C27. ¹H NMR (400 MHz, dmso-d₆) δ 12.80 (br. s, 1 H), 10.16 (s, 1 H), 8.12 (s, 1 H), 7.50 (s, 1 H), 7.37 (d, 1 H), 7.15 - 7.24 (m, 1 H), 6.92 (dd, 1 H), 3.90 (s, 3 H).

Step 5. Synthesis of 5-hydroxy-3-methoxy-2-naphthamide (P5),

A suspension of compound C27 (80 g, 360 mmol) in a mixture of DMF (15 ml) and dry THF (2 I) was treated with oxalyl chloride (64 ml) at about 25 ° C. The resulting suspension was stirred for about 1 h, then concentrated to dryness, and the residue was suspended in 2 I of dry THF and cooled on ice. Concentrated ammonium hydroxide (220 ml) was added over a period of about 5 to 10

-91minutes Then, the resulting mixture was stirred at about 25 ° C for approximately 20 more minutes. NaHCO was added₃ saturated aqueous (100 ml), and the THF was evaporated under reduced pressure. Water (1 I) was added, and the precipitate was filtered, washed with water and dried in vacuo. The resulting solid was suspended in EtOAc and heated at reflux for about 2 h. The solid was filtered, washed with EtOAc and dried to obtain the title compound P5. Yield: 51 g (65%) By repeating these steps, 1.0 kg of P5 was prepared.¹H NMR (400 MHz, dmso-d_and) δ 10.19 (s, 1 H), 8.21 (s, 1 H), 7.80 - 7.81 (br. s, 1 H), 7.60 - 7.61 (br. s, 1 H), 7.51 (s, 1 H), 7.38 - 7.41 (d, 2 H), 7.19 - 7.20 (t, 1 H), 6.97 - 6.99 (d, 1 H), 3.96 (s, 3 H).

Synthesis of 5-hydroxy-3-isopropoxy-2-naphthamide (P6).

<img file="CU20160149A7_D0043.tif" />

This compound was prepared in the same manner as compound P5, substituting 2propanol for MeOH in the reaction of compound C25 in Step 3 to obtain the title compound P6. ¹H NMR (400 MHz, dmso-d₆) δ 9.00 - 10.8 (br. s, 1 H), 8.28 (s, 1 H), 7.69 (s, 1 H), 7.61 (s, 1 H), 7.55 (s, 1 H), 7.35 - 7.37 ( d, 1 H), 7.16-7.20 (t, 1 H), 6.90-6.91 (d, 1 H), 4.80-4.86 (m, 1 H), 1.39-1.41 (d, 1 H).

Preparation 6: 1-Chloro-7-ethoxy¡soquinol¡n-6-carbonitr¡lo (P7)

Cl

N

<img file="CU20160149A7_D0044.tif" />

Step 1. Synthesis of 1-chloro-7-hydroxyisoquinolin-6-carbonitrile (C28). To a stirred solution of compound P2 (10.0 g, 40.6 mmol) in 250 ml of DCM, was added

-92 anhydrous aluminum (16.3 g, 122 mmol). The reaction mixture was heated at reflux for about 4 h. The supernatant liquid was removed by decantation, and ice was added to the residue remaining in the flask that was manually disintegrated to obtain a light yellow suspension. The solid was filtered and washed with water, dried and washed with ether to obtain the title compound C28. Yield: 8.1 g (97%)¹H NMR (400 MHz, dmso-d₅) δ 11.95 (s, 1 H), 8.65 (s, 1 H), 8.22 (d, 1 H), 7.84 (d, 1 H), 7.69 (s, 1 H).

Stage 2. Synthesis of 1-chloro-7-ethoxyisoquinolin-6-carbonyltrophil (P7). To a stirred solution of compound C28 (9.0 g, 44.1 mmol) in 190 ml of DMF, potassium t-butoxide (6.9 g, 61.8 mmol) was added at 0 ° C. After about 15 minutes, iodoethane (8.8 mL, 110 mmol) was added. The reaction mixture was heated to about 25 ° C and stirred for about 4 h. The reaction mixture was diluted with water, and the resulting precipitate was filtered and dried. Then, the precipitate was triturated with a mixture of MeOH and diethyl ether (9/1, v / v) to obtain the title compound P7. Yield: 7.6 g (83%)¹H NMR (400 MHz, dmso-d₅) δ 8.72 (s, 1 H), 8.31 (d, 1 H),

7.90 (d, 1 H), 7.62 (s, 1 H), 7.62 (s, 1 H), 4.37 (q, 2 H), 1.47 (t, 3 H).

Synthesis of 1-Chloro-7- (prop-2-in-1-yloxy) isoquinolin-6-carbonyl (P8).

X

This compound was prepared in the same manner as compound P7, substituting 3bromoprop-1-ina for iodoethane in the reaction of compound C28 in Step 2, to obtain the title compound P8.¹H NMR (400 MHz, dmso-d₆) δ 8.78 (s, 1 H), 8.34 (d, 1 H), 7.93 (d, 1 H), 7.84 (s, 1 H), 5.25 (s, 2 H), 3.79 (s, 1 H).

Synthesis of 1-chloro-7-methox-d3-isoquinolin-6-carbonitrile (P9).

CD₃ Cl ii

-93 This compound was prepared in the same manner as compound P7, substituting methyl 4-methylbenzenesulfonate-d₃ by iodoethane in the reaction of compound C28 in Step 2, to obtain the title compound P9. ¹H NMR (400 MHz, dmso-d₆): δ

8.73 (s, 1 H), 8.31 (d, 1 H), 7.91 (d, 1 H), 7.63 (s, 1 H).

Synthesis of 1-Chloro-7- (2-methoxyethoxy) isoquinnol-6-carbonyl (P10).

<img file="CU20160149A7_D0045.tif" />

This compound was prepared in the same manner as compound P7, substituting 1-bromo-2-methoxyethane for Iodoethane in the reaction of compound C28 in Step 2, to obtain the title compound P10. ¹H NMR (400 MHz, CDCI₃) δ 8.28 (d, 1 H),

8.16 (s, 1 H), 7.70 (s, 1 H), 7.56 (d, 1 H), 4.40 (t, 2 H), 3.90 (t, 2 H), 3.51 (s, 3 H).

Preparation 7; 1-chloro-7- (cyclopropylmethoxy) soquinol-6-carbontrtr (P11)

<img file="CU20160149A7_D0046.tif" />

Stage 1. Synthesis of 1-chloro-7- (cyclopropylmethoxyijisoquinolin-6-carbonitrile (PH).

A solution of triphenylphosphine (0.78 g, 3.0 mmol) in THF (8 ml) was treated with diisopropylazodicarboxylate (0.61 g, 3 mmol). After about 5 minutes, cyclopropyl methanol (0.29 g, 4.0 mmol), and then compound C28 (0.41 g, 2.0 mmol) was added. The mixture was heated for about 1.5 h, then cooled and concentrated. The residue was triturated with MeOH and filtered to obtain the title compound P11.¹H NMR (400 MHz, dmso-d₆) δ 8.75 (s, 1 H), 8.31 (d, 1 H), 7.91 (d, 1 H),

7.64 (s, 1 H), 4.20 (d, 1 H), 1.35 (m, 1 H), 0.65 (d, 2 H), 0.46 (d, 2 H),

Synthesis of 1-chloro-7-tert-butoxy-soquinol-6-carbonitrile (P12).

-94o.

<img file="CU20160149A7_D0047.tif" />

This compound was prepared in the same manner as compound P11, substituting

2-methyl-2-ropanol by cyclopropyl methanol in the reaction of compound C28 in Step 1, to obtain the title compound P12. ¹H NMR (400 MHz, CDCI₃) δ 8.29 (d, 1 H), 8.17 (s, 1 H), 7.97 (s, 1 H), 7.58 (d, 1 H), 1.63 (s, 9 H)

Synthesis of 1-chloro-7-cyclobutoxyisoquinol-n-6-carbonyl (P13).

<img file="CU20160149A7_D0048.tif" />

This compound was prepared in the same manner as compound P11, substituting cyclobutanol for cyclopropyl methanol in the reaction of compound C28 in Step 1, to obtain the title compound P13. ¹H NMR (400 MHz, dmso-d₆) δ 8.75 (s, 1 H),

8.31 (d, 1 H), 7.91 (d, 1 H), 7.50 (s, 1 H), 5.10 (quin, 1 H), 2.60 - 2.56 (m, 2 H), 2.26 2.18 (m, 2 H) , 1.93-1.83 (m, 1 H), 1.83-1.73 (m, 1 H).

Synthesis of 1-chloro-7- (oxetan-3-yloxy) isoquinolin-6-carbonyl (P14).

<img file="CU20160149A7_D0049.tif" />

This compound was prepared in the same manner as compound P11, substituting oxetan-3-ol for cyclopropyl methanol in the reaction of compound C28 in Step 1, to obtain the title compound P14. ¹H NMR (400 MHz, dmso-d₆) δ 8.81 (s, 1 H),

8.35 (d, 1 H), 7.94 (d, 1 H), 7.27 (s, 1 H), 5.63 - 5.81 (m, 1 H), 5.06 (t, 1 H), 4.69 (m, 2 H).

Preparation 8: 4-Chloro-6-Sopropoxyquinoline-7-Carbonitrile (P15)

<img file="CU20160149A7_D0050.tif" />

Stage 1. Synthesis of 4-chloro-6-isopropoxyquinolin-7-carbonitrlo (P15)

Phosphorus oxychloride (28.2 ml, 303 mmol) was added dropwise with stirring to a solution of compound P4 (20 g, 75.8 mmol), pyridine (91 ml, 1.13 mol) and imidazole (10.3 g, 151.5 mmol) in DCM (300 ml). The mixture was stirred at about 25 ° C for about 30 minutes. Then, the reaction mixture was cooled on ice and quenched with cold water (100 ml), added slowly to maintain the temperature approximately below 5 ° C. Stirring continued for approximately 20 more minutes and cooled. Then, the mixture was poured into 1 M HCI (500 ml) and separated. The aqueous phase was extracted with DCM. The combined DCM extracts were washed with 1M HCI, water, Na solution.₂CO₃, brine, dried in Na₂SW₄, filtered and concentrated to obtain the title compound P15. Yield: 12 g (64%)¹H NMR: (400 MHz, CDCI₃) δ 8.70 (d, 1 H), 8.41 (s, 1 H), 7.54 (d, 1 H), 7.52 (s, 1 H), 4.85 (quin, 1 H), 1.50 (d, 6 H).

Preparation 9: 4-Chloro-6-methoxyquinoline-7-carbonyl (P16)

Stage 1. Synthesis of 4-chloro-6-hydroxyquinol-7-carbonyl (C29)

To an stirred solution of compound P15 (12.0 g, 48.6 mmol) in 180 ml of DCM, anhydrous aluminum chloride (20.6 g, 155 mmol) was added. The reaction mixture was heated at reflux overnight. The solvent was evaporated under reduced pressure, and the residue was stirred with 0.1 M HCI (400 mL) at 25 ° C for 2 h. The remaining solid was filtered, washed with water, MeOH and dried to obtain the title compound C29. Yield: 9.6 g (96%)¹H NMR: (400 MHz, dmso-d₆) δ 11.82 (s, 1 H), 8.74 (d, 1 H);

8.56 (s, 1 H), 7.81 (d, 1 H), 7.60 (s, 1 H).

Stage 2. Synthesis of 4-chloro-6-methoxyquinoline-7-carbonyl (P16)

To a stirred solution of compound C29 (9.6 g, 46.9 mmol) in DMF (190 mL), potassium t-butoxide (6.8 g, 61 mmol) was added at 0 ° C. After about 15 minutes, iodomethane (7.3 m „117 mmol) was added. The reaction mixture was heated to about 25 ° C and stirred for about 2 h. The reaction mixture is

-96 diluted with water, and the resulting precipitate was filtered and dried. The solid was washed with water, hexane and dried under vacuum to obtain the title compound P15. Yield: 8.1 g (79%)¹H NMR: (400 MHz, CDCI₃) δ 8.73 (d, 1 H), 8.41 (s, 1 H),

7.56 (d, 1 H); 7.52 (s, 1 H), 4.09 (s, 3 H).

Synthesis of 4-chloro-6-ethoxyquinolin-7-carbonitrile (P17).

This compound was prepared in the same manner as compound P16, substituting iodoethane for iodomethane in the reaction of compound C30 in Step 3, to obtain the title compound P17.¹H NMR: (400 MHz, dmso-d_and) δ 8.72 (s, 1 H), 8.31 (d, 1 H), 7.89 (d, 1 H), 7.62 (s, 1 H), 4.38 (q, 2 H), 1.46 (t, 3 H).

Preparation 10; 1-Chloro-7- (dfluoromethoxy) isoquinoline-6-carbonitrile (P18)

Step 1. Synthesis of 1-chloro-7- (difluoromethoxy) isoquinolin-6-carbonitrile (P18).

A solution of compound C27 (164 mg, 0.8 mmol) in DMF (2 mL) was treated with sodium difluoroacetate (95 mg, 0.8 mmol) and cesium carbonate (285 mg, 0.9 mmol). The mixture was heated at about 60 ° C for about 1 h. The mixture was diluted with 25 ml of water and 25 ml of EtOAc, and the EtOAc separated, washed with brine, dried over Na₂SW₄, was filtered and concentrated. The residue was purified by column chromatography to obtain the title compound P18. Yield: 133 mg (65%).¹H NMR: (400 MHz, dmso-d₆) δ 8.93 (s, 1 H), 8.48 (d, 1 H), 8.07 (d, 1 H), 8.02 (dd, 1 H), 7.70 (t, 1 H).

Preparation 11: 6-Bromo-1-Chloro-7- (trifluoromethoxy) isoquinoline (P19)

-97F

F

<img file="CU20160149A7_D0051.tif" />

Br

Stage 1. Synthesis of 6-bromo-1-clQro-7- (trifluoromethoxy) isoquinoline (P19). A suspension of 6-bromo-7- (trfluoromethox¡) soqunolnol-1 (2H) -one (CAS 1445564-99-7, 410 mg, 1.3 mmol) in 6 ml of POCI₃ It was heated at reflux for about 40 minutes. The mixture was cooled in ice, and then poured into ice water with vigorous stirring. After the ice melted, the mixture was extracted with EtOAc (100 ml). The EtOAc was separated and stirred with saturated aqueous NaHCO solution.₃ (100 ml) until no more bubbling occurred. The EtOAc was separated, washed with brine, dried over Na₂SW₄, was filtered and concentrated. The residue was purified by silica chromatography to obtain the title compound P19. Yield: 130 mg (31%)¹H NMR (400 MHz, CDCI₃) δ 8.36 (d, 1 H), 8.24 (d, 1 H), 8.22 (s, 1 H), 7.56 (d, 1 H).

Preparation 12: 1-Chloro-7-cyclopropox¡isoquinol¡n-6-carbon¡tr¡lo (P21)

Step 1. Synthesis of 1-chloro-7- (2-chloroethoxy) isoquinoline-6-carbonyl (C166).

A mixture of compound C28 (2.4 g, 11.8 mmol), 2-chloroethanol-1- (4-methylbenzenesulfonate) (CAS 80-41-1, 5.5 g, 23.5 mmol), Triton-405 was heated (6.63 g, 11.8 mmol) and cesium carbonate (4.58 g, 14.1 mmol) in 96 ml of THF for about 8 h at about 65 ° C. The mixture was diluted with water and extracted with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C166. Yield: 2.0 g (64%). LCMS: MH⁺ = 267.0.

Step 2. Synthesis of 1-chloro-7- (vinyloxy) isoquinolin-6-carbonitrile (C167),

A solution of compound C166 (1.4 g, 5.3 mmol) in THF (50 ml) was treated with a solution of potassium t-butoxide (1.2 g, 10.6 mmol) in 15 ml of THF at around 20 ° C, then the mixture was heated to about 25 ° C and stirred for about 1 h. NH added₄Saturated aqueous CI, and the mixture was extracted with EtOAc. The

-98 combined EtOAc extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C167. Yield: 1.1 g (90%). LCMS: MH⁺ = 230.9.

Stage 3. Synthesis of 1-chloro-7-cyclopropox¡soqu¡nol¡n-6-carbon¡tr¡lo (P21).

A solution of compound C167 (220 mg, 0.9 mmol) was treated sequentially in 50 ml of DCM at about 0 ° C with ethereal diazomethane (150 ml), then with palladium acetate (ll) (25 mg). The mixture was stirred overnight at about 25 ° C, then the mixture was filtered and concentrated. The residue was purified by chromatography to obtain the title compound P21. Yield: 30 mg (13%).¹H NMR (400 MHz, dmso-d₆) δ 8.22 - 8.21 (d, 1 H), 8.09 (s, 1 H), 7.98 (s, 1 H), 7.51 - 7.50 (d, 1 H),

3.99-3.95 (m, 1 H), 0.97-0.88 (m, 4 H).

Preparation 13: 3,4-dichloro-6-methoxyquinoline-7-carbonitrile (P22)

<img file="CU20160149A7_D0052.tif" />

Stage 1, Synthesis of 3-chloro-7-iodo-6-methoxyquinoline-4 (1H) -one (C168).

A solution of 7-iodo-6-methoxyquinolin-4 (1H) -one (CAS 1300031-68-8, 2.0 g, 6.6 mmol) and N-chlorosuccinimide (976 mg, 7.3 mmol ) in AcOH (20 ml) was heated at about 35 ° C for about 18 h. It was filtered, and the precipitate was dried to obtain the title compound C168. Yield: 1.4 g (63%).¹H NMR (400 MHz, dmso-d₆) δ 12.25 (br. s, 1 H), 8.35 (s, 1 H), 8.11 (s, 1 H), 7.47 (s, 1 H), 3.91 (s, 3 H). Step 2. Synthesis of 3,4-dichloro-6-methoxyquinoline-7-carbonyl (P22).

A mixture of compound C168 (2.6 g, 7.7 mmol) and cuprous cyanide (1.31 g, 15.5 mmol) in pyridine (26 ml) was heated at about 120 ° C for about 16 h. The mixture was cooled to about 25 ° C, filtered, and the filtrate was concentrated. The residue was suspended in toluene and concentrated, then treated with POCI.₃ (15 ml, 160 mmol) and triethylamine hydrochloride (1.47 g, 10.7 mmol). The mixture was heated at reflux for about 3 h, then cooled to about 25 ° C and concentrated. The residue was stirred with NaHCO₃ aqueous. The resulting precipitate was filtered, washed with n-hexane and dried in vacuo. The dried solid was suspended in a 9/1 MeOH / DCM ratio and NaHCO was added₃ solid. This mixture was stirred for about 5 h, filtered, and the

-99filtrate was concentrated. The residue was triturated with diethyl ether and dried in vacuo to obtain the title compound P22. Yield: 1.5 g (56%).¹H NMR (400 MHz, dmso-d₆) δ 8.98 (s, 1 H), 8.71 (s, 1 H), 7.60 (s, 1 H), 4.11 (s, 3 H).

Preparation 14: 4-bromo-l-chloro-7-isopropoxisoisoolin-6-carbonitri (P23)

Br

Step 1. Synthesis of 7-isopropoxy-1-oxo-1,2-dihydroisoquinoline-6-carbonitrile (C169).

A solution of compound P2 (10.0 g, 40 mmol) and hydrogen chloride in 1,4-dioxane (4 M, 100 ml) in water (100 ml) was heated in a sealed tube at about 120 ° C for about 18 h. The mixture was cooled to about 25 ° C and diluted with water. The precipitate was filtered, washed with water and dried to obtain the title compound C169. Yield: 7.5 g (81%).¹H NMR (300 MHz, dmso-d₆) δ

11.5 (br. S, 1 H), 8.21 (s, 1 H), 7.77 (s, 1 H), 7.12 - 7.16 (t, 1 H), 6.53 - 6.56 (d, 1 H),

4.85-4.93 (m, 1 H), 1.35-1.37 (d, 6 H).

Step 2. Synthesis of 4-bromo-7-isopropoxy-1-oxo-1,2-dihydroisoquinolin-6-carbonitrile (C170).

A solution of N-bromosuccinimide (14 g, 78 mmol) in acetonitrile (150 ml) was added dropwise to a suspension of compound C169 (15 g, 65 mmol) in acetonitrile (1.38 I) at about 25 ° C and stirred for about 24 h to obtain a yellow suspension. The reaction mixture was concentrated to half the volume. The precipitate was filtered, washed with diethyl ether and dried to obtain the title compound C170. Yield: 13.0 g (65%).¹H NMR (400 MHz, dmso-d₆) δ 11.8 (br. s, 1 H), 8.08 (s, 1 H), 7.84 (s, 1 H), 7.52 - 7.53 (d, 1 H), 4.92 - 4.98 (m, 1 H),

1.36-1.38 (d, 6 H).

Step 3. Synthesis of 4-bromo-1-chloro-7-sopropoxyisoquinol-6-carbonitrile (P23).

A suspension of compound C170 (10.0 g, 32 mmol) in POCI₃ (120 ml) was heated at reflux for about 1.5 h. The mixture was concentrated, and the residue was dissolved in

DCM The DCM extract was washed with K2CO3, brine, dried over Na₂SW₄, was filtered and concentrated. The residue was purified by chromatography to obtain the

-100composite of title P23. Yield: 9 g (85%).¹H NMR (400 MHz, CDCI₃) δ 8.49 (s, 1 H), 8.42 (s, 1 H), 7.65 (s, 1 H), 4.87-493 (m, 1 H), 1.52 - 1.53 (d, 6 H).

Preparation 15: 4-hydroxy-6-methoxyisoquinolin-7-carbonitrile (P24)

<img file="CU20160149A7_D0053.tif" />

Step 1. Synthesis of 2 - ((3-bromo-4-methoxybenzyl) amino) ethyl acetate (C173).

To a solution of glycine ethyl ester hydrochloride (17 g, 126 mmol) and Et₃N (25.2 g, 252 mmol) in DCM (100 ml) and MeOH (100 ml), sodium triacetoxyborohydride (53.1 g, 252 mmol) was added at about 0 ° C. The mixture was stirred for about 30 min before 3-bromo-4-methoxybenzaldehyde (26.8 g, 126 mmol) was added, then the mixture was heated at about 25 ° C for about 18 h. Water (200 ml) and NH were added₄Saturated aqueous Ci (100 ml), and the mixture was extracted with DCM. The combined DCM extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C173. Performance; 15 g (45%).¹H NMR (400 MHz, dmso-d₆) δ 7.52 (d, 1 H), 7.26 (dd, 1 H), 7.05 (d, 1 H), 4.08 (q, 2 H), 3.82 (s, 3 H),

3.64 (s, 2 H), 3.27 (s, 2 H), 2.67 (br. S., 1 H), 1.19 (t, 3 H).

Step 2, Synthesis of 2- (N- (3-bromo-4-methoxybenzyl) -4-methylphenylsulfonamido) ethyl acetate (C174).

To a solution of compound C173 (18 g, 60 mmol) and pyridine (24 g, 298 mmol) in THF (400 ml), tosyl chloride (11.4 g, 60 mmol) was added at 0 ° C. The mixture was stirred for about 16 h at about 25 ° C, then acidified to about pH 3 with concentrated HCI and extracted with DCM (3 x 300 mL). The combined DCM extracts were washed with brine, dried over Na₂SW_4l They were filtered and concentrated. The residue was purified by chromatography to obtain the title compound C174. Yield: 17 g (63%).¹H NMR (400 MHz, CDCI₃) δ 7.68 (d, 2 H), 7.26 (d, 2 H), 7.19 (s, 1 H), 7.11 (dd, 1 H), 6.76 (d, 1 H), 4.33 (s, 2 H), 3.94 (q, 2 H), 3.83 (s, 2 H),

3.81 (s, 3 H), 2.37 (s, 3 H), 1.08 (t, 3 H).

Step_3._Acidic_Synthesis_2- (N- (3-bromo-4-methoxybenzyl) -4-methylphenylsulfonamidojacetic (C175). To a solution of compound C174 (17 g, 37 mmol) in THF (100 ml) and MeOH (100 ml), was added a solution of lithium hydroxide -101 (1.7 g, 74 mmol) in water (100 ml) at about 25 ° C. The mixture was stirred for about 4 h, then the mixture was partially concentrated to remove THF and MeOH The remaining solution was acidified to about pH 3 with concentrated HCl and extracted with DCM (3 x 100 mL). The combined DCM extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated to obtain the title compound C175. Yield: 15 g (94%).¹H NMR (400 MHz, CDCI₃) δ 7.75 (d, 2 H), 7.33 (d, 2 H), 7.27 (s, 1 H), 7.17 (d, 1 H), 6.83 (d, 1 H), 4.38 (s, 2 H), 3.93 (s, 2 H), 3.88 (s, 3 H),

2.43 (s, 3 H).

Step 4. Synthesis of 7-bromo-6-methox¡ ~ 2-tos¡l-2,3-d¡h¡dro¡soqu¡nol¡n-4 (1H) -one (C176).

To a solution of compound C1175 (4.27 g, 10 mmol) in DCM (120 ml), 2 drops of DMF were added, and then oxalyl chloride (6.3 g, 50 mmol) at about 25 ° C. After about 2 h, the mixture was evaporated. The residue was dissolved in DCM (100 ml) and cooled to about -78 ° C. Anhydrous aluminum chloride (3.32 g, 25 mmol) was added portionwise. The mixture was stirred for about 40 min at about -78 ° C, then stirred for about 2 h at about 0 ° C. Water was added, and the DCM separated, washed with brine, dried over Na₂SW₄, was filtered and concentrated. The residue was triturated with a mixture of MeOH (7.5 ml) and EtOAc (7.5 ml). The precipitate was collected by filtration and dried to obtain the title compound C176. Yield: 1.9 g (46%).¹H NMR (400 MHz, CDCI₃) δ 7.63 (d, 2 H), 7.47 (s, 1 H), 7.31 (s, 1 H), 7.27 (d, 2 H), 4.43 (s, 2 H), 3.99 (s, 2 H), 3.89 (s, 3 H), 2.39 (s, 3 H).

Stage 5. Synthesis of 7-bromo-6-methox¡soquinol¡n-4-ol (C177).

A mixture of compound C176 (1.9 g, 4.6 mmol) and NaHCO₃ (1.54 g, 18.5 mmol) in EtOH (50 mL) was heated at reflux for about 2 h, then cooled to about 25 ° C and concentrated. The residue was treated with EtOAc and water. The EtOAc was separated, and the aqueous phase was extracted with additional EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C177. Yield: 300 mg (26%).¹H NMR (400 MHz, dmso-d₆) δ 10.50 (br. s „1 H), 8.67 (s, 1 H), 8.39 (s, 1 H), 8.03 (s, 1 H), 7.47 (s, 1 H), 4.01 (s, 3 H ).

Step 6. Synthesis of 4-hydroxy-6-methoxyisoquinol-7-carbonitrile (P24),

A mixture of compound C177 (100 mg, 0.39 mmol), zinc cyanide (231 mg, 2 mmol) and tetrakis (triphenylphosphine) palladium (0) (45 mg, 0.04 mmol) in 5 mL of DMF was stirred.

-102 for about 10 min at about 25 ° C, then heated at about 140 ° C for about 6 h. The mixture was cooled, concentrated, and the residue was treated with water and extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na₂SW₄, was filtered and concentrated. The residue was purified by chromatography to obtain the title compound P24. Yield: 65 mg (82%).

¹H NMR (400 MHz, dmso-d₆) δ 10.74 (s, 1 H), 8.78 (s, 1 H), 8.71 (s, 1 H), 8.13 (s, 1 H),

7.53 (s, 1 H), 4.06 (s, 3 H).

Preparation 16: 8-fluoro-5-hydroxy-3-methoxy-2-naphthamide (P25)

Stage 1. Synthesis of methyl 5-hydrox-3-methoxy-2-naphthoate (C178)

A solution of compound C26 (40 g, 85 mmol) in THF (150 ml) was treated with tetra-n-butylammonium fluoride (31 g, 119 mmol) and stirred for 30 min at 25 ° C. The reaction mixture was neutralized with AcOH and then diluted with water and EtOAc. The EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C178. Yield: 16.50 g (89%).¹H NMR (400 MHz, dmso-d₆) δ 10.19 (s, 1 H), 8.21 (s, 1 H), 7.53 (s, 1 H), 7.39 - 7.42 (d, 1 H), 7.19 - 7.22 (t, 1 H), 6.96 (d, 1 H), 3.92 (s, 3 H),

3.85 (s, 3 H).

Step 2. Synthesis of methyl 8-fluoro-5-hydrox-3-methoxy-2-naphthoate (C179)

A solution of SelectFIuor (3.18 g, 8.6 mmol) in DMF (10 mL) was slowly added to a solution of compound C178 (2.00 g, 8.6 mmol) in DMF (20 mL) at about 0 ° C After stirring overnight, the mixture was diluted with brine and extracted with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C179. Yield: 90 mg (4%).¹H NMR (400 MHz, CDCI₃) δ

8.49 (s, 1 H), 7.52 (d, 1 H), 6.86 (dd, 1 H), 6.77 (dd, 1 H), 3.98 (s, 3 H), 4.02 (s, 3 H). ¹⁹F NMR (400 MHz, CDCI₃) δ -130.68.

Step 3. Synthesis of 8-fluoro-5-hydroxy-3-methoxy-2-naphthamide (P25)

A solution of compound C179 (90 mg, 0.36 mmol) in THF (4 mL) and water (2.5 mL) was treated with lithium hydroxide (88 mg, 3.6 mmol) at about 20 ° C. After stirring overnight, the mixture was acidified with 1 M HCI and concentrated to dryness. The residue was stirred in DCM (5 ml) and treated with oxalyl chloride solution (2 M, 0.27 ml) together with a catalytic amount of DMF. After about 1 h

-103 at about 20 ° C, the mixture was filtered and concentrated to dryness. The residue was absorbed in THF (2 ml) and treated with a solution of ammonia in dioxane (0.5 M, 1 ml) at about 20 ° C. After about 1 h, the mixture was filtered and concentrated. The residue was purified by chromatography to obtain the title compound P25. Yield: 27 mg (32%).¹H NMR (400 MHz, dmso-d_and) δ 10.17 (br. s., 1 H), 8.32 (s, 1 H), 7.81 (br. s., 1 H), 7.66 (br. s „1 H), 7.53 (s, 1 H), 7.00 (dd, 1 H),

6.82 (dd, 1 H), 3.98 (s, 3 H). ¹⁹F NMR (400 MHz, dmso-d₆) δ -134.39.

Preparation 17: (S) -3,3-dimethyl-1,7a-dihydropyrrolof1,2-c1oxazol-5 (3H) -one (P20)

Step 1. Synthesis of (S) -3,3-dimethyl-5- (trimethylsilyloxy) -1,3,7,7a-tetrahydropyrrolo [1,2-cxaxazole (C30) A solution of düsopropylamine (147 ml, 1.05 mol) in dry THF (875 ml) was cooled to about -25 ° C and treated with n-butyllithium (2.5 M in hexanes, 387 ml, 970 mmol). The mixture was stirred at about -20 ° C for about 30 minutes, then cooled to about -70 ° C. A solution of (S) -3,3dimethyltetrahydropyrrolo [1,2-c] oxazol-5 (1H) -one (CAS 99208-71-6, 125 g, 806 mmol) in THF (163 ml), was added, and the temperature was maintained approximately below -60 ° C. After the addition was complete, the mixture was stirred for approximately 5 more minutes before the addition of TMSCI (132 ml, 1.05 mol) at -60 ° C. Then, the mixture was heated to about -10 ° C before it was concentrated under reduced pressure. The residue was stirred with dry hexanes (1 i) and concentrated, then stirred again with dry hexanes (1 I) and concentrated. The residue was stirred with dry hexanes (1 I), filtered and concentrated under reduced pressure to obtain the title compound C30 that was used in Step 2 without further purification.¹H NMR (400 MHz, CDCI₃) δ 4.16 (m, 1 H), 4.00 (dd, 1 H), 3.75 (dd, 1 H), 3.56 (dd, 1 H), 2.54 (m, 1 H),

2.31 (dd, 1 H), 1.49 (s, 3 H), 1.36 (s, 3 H), 0.24 (s, 9 H).

Step 2. Synthesis of (S) -3,3-dimethyl-1,7a-dhydropyrrolo [1,2-cjoxazol-5 (3H) -one (P20) The crude compound C30 of Step 1 was dissolved in THF (915 ml) and treated with allyl methyl carbonate (104 ml, 911 mmol) and palladium acetate (11) (9.0 g, 40 mmol). The mixture was heated to about 65 ° C until the evolution of gas ceased and then heated for another 1 h after the evolution of gas ceased. Then the mixture cooled.

-104 to about 25 ° C and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the title compound P20. Yield: 90 g (73%)¹H NMR (400 MHz, CDCI₃) δ 7.07 (dd, 1 H) 6.09 (dd, 1 H)

4.60 - 4.71 (m, 1 H) 4.13 (dd, 1 H) 3.33 (dd, 1 H) 1.67 (s, 3 H) 1.56 (s, 3 H).

Preparation 18: (5S) -5- (hydroxymethyl) -3-methylpyrrolidine-2-one (L1)

HO

OR

Stage 1. Synthesis of (7aS) -3,3,6-trimethyltetrah-dropyrrolof1,2-c1oxazol-5 (3H) -one (C31).

To a solution of (S) -3,3-dimethyltetrahydropyrrolo [1,2-c] oxazol-5 (1 H) -one (CAS 9920871-6, 3.0 g, 19 mmol) in 50 ml of THF, LDA (2M, 12.1 ml, 20 mmol) was added at about -78 ° C. The reaction mixture was stirred for about 30 minutes, and then odomethane (3.03 g, 21 mmol) was added. The reaction mixture was maintained for about 10 minutes at about -78 ° C, then heated at about 25 ° C for about 1 h. The reaction was quenched by the addition of EtOAc (10 ml) and water (10 ml). The EtOAc was separated, and the aqueous phase was extracted with additional EtOAc (50 ml x 2). The combined EtOAc extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated to obtain the title compound C31. Yield: 3.1 g (92%).¹H NMR (400 MHz, CDCI₃) δ 4.11 (m, 2 H), 3.42 (m, 1 H), 2.87 (dt, 1 H), 2.38 (m, 1 H), 1.65 (s, 3 H), 1.46 (s, 3 H), 1.36 (m, 2 H), 1.20 (s, 1.5 H), 1.19 (s, 1.5 H).

Step 2 Synthesis of (5S) -5- (hydroxymethyl) -3-methylpyrrolidin-2-one (L1), A solution of compound C31 (58 mg, 0.34 mmoi) in MeOH (1.1 ml) is treated with 4-toluenesulfonic acid (1.4 mg, 7 pmol). The resulting mixture was stirred at 60 ° C for about 4 h. The mixture was concentrated in vacuo to obtain the title compound L1. Yield: 38 mg (86%)¹H NMR (400 MHz, CDCI₃) δ 3.70 - 3.83 (m, 2 H),

3.39 - 3.49 (m, 1 H), 2.51 - 2.64 (m, 1 H), 2.30 - 2.42 (m, 1 H), 1.34 - 1.46 (m, 1 H),

1.23 (s, 1.5 H), 1.21 (s, 1.5 H),

Synthesis of (5S) -3-fiuoro-5- (h¡drox¡metii) pyrrolidin-2-one (L2).

-105 This compound was prepared in the same manner as compound L1, substituting

NFSI for ¡odometano in Stage 1. ¹H NMR (400 MHz, CD₃OD) δ 5.24 - 5.11 (m, 1

H), 3.83-3.32 (m, 3 H), 2.68-1.88 (m, 2 H).

Synthesis of (3R, 5R) -3-fluoro-5- (hydroxymethyl) pyrrolin-2-one (L3)

HN

This compound was prepared in the same manner as compound L1, substituting (R) -3,3-dimethyltetrahydropyrrolo [1,2-c] oxazol-5 (1H) -one (CAS 103630-36-0, Chemical Communications , 2011, 47, 10037-10039) for (S) -3,3-dimethltratra-hydroplrolo [1,2c] oxazol-5 (1H) -one (CAS 99208-71-6), and NFSI for ¡odomethane , in Stage 1, and then the diastereomeric products were separated. ¹H NMR (400 MHz, CDCI₃) δ 4.96 5.16 (m, 1 H), 3.64 - 3.72 (m, 2 H), 3.41 - 3.49 (m, 1 H), 2.53 - 2.63 (m, 1 H), 1.85 2.02 (m, 1 H).

Synthesis of (5S) -3-ethyl-5- (hydroxylmethyl) pyrrolin-2-one (L4).

<img file="CU20160149A7_D0054.tif" />

This compound was prepared in the same manner as compound L1, replacing bromoethane with ¡odomethane in Step 1. ¹H NMR (400 MHz, CDCI₃) δ 4.03 - 4.17 (m, 2 H), 3.37 - 3.47 (m, 1 H), 2.69 - 2.83 (m, 1 H), 2.51 - 2.65 (m, 1 H), 2.37 (s, 1 H),

1.86 - 1.96 (m, 1 H), 1.33 - 1.44 (m, 1 H), 1.02 (t, 1 H), 0.95 (t, 3 H).

Synthesis of (5S) -5- (hydroxymethyl) -3- (methoxymethyl) pyrrolin-2-one (L5).

<img file="CU20160149A7_D0055.tif" />

This compound was prepared in the same manner as compound L1, replacing chlorine (methoxy) methane with ¡odomethane in Step 1. ¹H NMR (400 MHz, CDCI₃) δ 3.63

-106- 3.84 (m, 2 Η), 3.46 - 3.63 (m, 2 Η), 3.38 (s, 3 Η), 2.64 - 2.75 (m, 1 Η), 2.17 - 2.39 (m, 2 Η), 1.75 -2.05 (m, 1 Η).

Synthesis of (3R, 5S) -5- (hydroxymethyl) -3- (2-hydroxypropan-2-yl) pyrrolidin-2-one (L11).

<img file="CU20160149A7_D0056.tif" />

ΌΗ

This compound was prepared in the same manner as compound L1, replacing acetone with iodomethane in Step 1. ¹H NMR (400 MHz, CDCI₃) δ 6.27 - 6.42 (m, 1 H), 3.62 - 3.77 (m, 2 H), 3.50 - 3.59 (m, 1 H), 2.59 - 2.72 (m, 1 H), 1.92 - 2.04 (m, 2 H ),

1.23 (s, 6 H).

Synthesis of (5S) -3 - ((benzyloxy) methyl) -5- (hydroxymethyl) pyrrolidine-2-one (L12).

<img file="CU20160149A7_D0057.tif" />

This compound was prepared in the same manner as compound L1, replacing CAS 3587-60-8 ("benzyloxymethyl chloride") with iodomethane in Step 1. ¹H NMR (400 MHz, CDCIs) δ 7.27 - 7.41 (m, 5 H), 6.58 (br. S., 1 H), 4.46 - 4.63 (m, 2 H), 3.61 3.85 (m, 4 H), 3.41 - 3.53 (m, 1 H), 2.66 - 2.80 (m, 1 H), 2.30 (m, 1 H), 1.98 (s, 1 H). Synthesis of (3S, 5S) -3-hydroxy-5- (hydroxymethyl) pyrrolidine-2-one (L13).

<img file="CU20160149A7_D0058.tif" />

This compound was prepared in the same manner as compound L1, replacing CAS 104372-31-8 with iodomethane in Step 1. ¹H NMR (400 MHz, dmso-d₆) δ 4.41 (dd, 1 H), 4.07 (dd, 1 H), 3.82 - 3.93 (m, 1 H), 3.34 - 3.42 (m, 1 H), 2.41 - 2.49 (m, 1 H),

1.45-1.53 ​​(m, 1 H).

Synthesis of (3R, 5S) -3-hydroxy-5- (hydroxymethyl) pyrrolidin-2-one (L14).

-107HO—^/

This compound was prepared in the same manner as compound L1, substituting

CAS 127184-05-8 by iodomethane in Stage 1. ¹H NMR (400 MHz, dmso-d₆) δ 5.79 (d, 1 H), 4.22 - 4.32 (m, 1 H), 4.16 (td, 1 H), 4.01 (dd, 1 H), 3.32 - 3.36 (m, 1 H), 3.17 (d, 1 H), 1.84-1.95 (m, 2 H).

Synthesis of (3S, 5S) -5- (hydroxymethyl) -3- (2,2,2-trifluoroethyl) pyrrol¡d¡n-2-one (L15) and (3R, 5S) -5- (h Droxymethyl) -3- (2,2,2-trifluoroethyl) pyrrolidin-2-one (L16),

HN „_ΛΟΗ

<img file="CU20160149A7_D0059.tif" />

<img file="CU20160149A7_D0060.tif" />

OR

HO

These compounds were prepared in the same manner as compound L1, substituting 1,1,1-trifluoro-2-iodoethane, which was added slowly, by iodomethane in Step 1, and then the diastereomeric products were separated by gel chromatography. silica before Stage 2. Application of Stage 2 to individual diastereomers produced the title compounds L15 and L16. L15¹H NMR (400 MHz, CDCI₃) δ 6.48 (br. s., 1 H), 3.67-3.79 (m, 2 H), 3.52-3.62 (m, 1 H),

2.74 - 2.91 (m, 2 H), 2.28 (dd, 1 H), 1.99 - 2.15 (m, 2 H). L16:¹H NMR (400 MHz, CDCb) δ 6.12 (br. S., 1 H) 3.77 - 3.86 (m, 2 H) 3.43 - 3.52 (m, 1 H) 2.83 - 2.98 (m, 1 H)

2.71 - 2.82 (m, 1 H) 2.45 - 2.56 (m, 1 H) 1.99 - 2.15 (m, 1 H) 1.89 (dd, 1 H) 1.51 - 1.58 (m, 1 H).

Synthesis of (5S) -5- (hydroxymethyl) -3- (4-hydroxytetrahydro-2H-pyran-4-yl) pyrrolidine-2-one

0=201

Ο-Λ

<img file="CU20160149A7_D0061.tif" />

This compound was prepared in the same manner as compound L1, substituting tetrahydro-4H-pyran-4-one (CAS 29943-42-8) for iodomethane in Step 1. 1H NMR (400 MHz, CDaCN) δ 4.30 (d , 1 H), 3.60 - 3.77 (m, 4 H), 3.51 - 3.60 (m, 1 H), 3.43 1083.51 (m, 1 Η), 3.34 - 3.42 (m, 1 Η), 2.93 (t, 1 Η ), 2.51 (t, 1 Η), 1.98 - 2.08 (m, 1 Η), 1.86 - 1.94 (m, 2 Η), 1.80 (ddd, 1 Η), 1.58 - 1.69 (m, 1 Η), 1.41 - 1.52 (m, 1 Η), 1.24 (dd, 1 Η).

Synthesis of (5S) -5- (h¡drox¡met¡l) -3- (3-h¡drox¡oxetan-3-il) p¡rrol¡din-2-one (L22).

<img file="CU20160149A7_D0062.tif" />

This compound was prepared in the same manner as compound L1, replacing CAS 6704-31-0 (oxetan-3-one) with iodomethane in Step 1 to obtain (6S, 7aS) -6 (3-hydroxoxetan -3-¡) -3,3-d-methyltetrahydropyrroium [1,2-c] oxazol-5 (3H) -one (C81), which was used in Step 2. ¹H NMR (400 MHz, dmso-d₆) δ 5.82 (d, 1 H), 4.70 - 4.80 (m, 2 H),

4.46 (d, 1 H), 4.36 - 4.44 (m, 2 H), 3.42 (dd, 1 H), 3.27 - 3.31 (m, 1 H), 2.80 - 2.91 (m, 1 H), 1.83 - 1.98 ( m, 2 H).

Synthesis of (5S) -3-benzyl-5- (h¡droximetiQp¡rrol¡d¡n-2-one (L28).

<img file="CU20160149A7_D0063.tif" />

This compound was prepared in the same manner as compound L1, substituting benzyl bromide for iodomethane in Step 1. ¹H NMR (400 MHz, dmso-d₆) δ

7.64 (s, 1 H), 7.31 (t, 2 H), 7.24 (m, 3 H), 4.74 (t, 1 H), 3.16 (q, 2 H), 3.02 (dd, 1 H),

2.64 (m, 2 H), 2.54 (s, 1 H), 1.82 (m, 2 H).

Synthesis of (3R, 5S) -3-fluoro-5- (hydroxymethyl) -3- (tetrahydro-2H-pyran-4-yl) pyrrolidin-2-one

U1L

<img file="CU20160149A7_D0064.tif" />

This compound was prepared in the same manner as compound L1, substituting compound C49 for compound C30, and NFSI with iodomethane in Step 1. ¹H NMR (400 MHz, CDCI₃) δ 4.03 (dd, 1 H), 3.98 (d, 1 H), 3.73 (d, 1 H), 3.66 - 3.64 (m, 1 H),

-1093.58 - 3.55 (m, 1 Η), 3.47 - 3.38 (m, 2 Η), 2.51 - 2.40 (m, 1 Η), 2.32 - 2.26 (m, 2 Η),

1.91 (ddd, 1 Η), 1.80 (d, 1 Η), 1.56-1.36 (m, 2 Η).

Preparation 19: (3S, 5S) -3-ethyl-3-fluoro-5- (hydroxymethyl) pyrrolidine-2-one (L7)

HO

OR

Stage 1. Synthesis of (7aS) -6-eti-3,3-dimethyltrahydropyrrolof1,2-cjoxazol-5 (3H) -one (C32).

To a solution of (S) -3,3-dimethyltetrahydropyrrolo [1,2-c] oxazol-5 (1H) -one (CAS 9920871-6, 1.0 g, 6.4 mmol) in 30 ml of THF, LDA (2M, 4.0 mL, 8.0 mmol) was added at about -78 ° C. The reaction mixture was stirred for about 30 minutes, then bromoethane (0.80 g, 7.2 mmol) was added. The reaction mixture was maintained for about 10 minutes at about -78 ° C, then heated at about 25 ° C for about 25 minutes. The reaction was quenched by the addition to EtOAc (10 ml) and water (10 ml). The EtOAc was separated, and the aqueous phase was extracted with additional EtOAc (50 mL x 2). The combined EtOAc extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated to obtain the title compound C32. Yield: 0.80 g (68%)¹H NMR (400 MHz, CDCI₃) δ 4.04-418 (m, 2 H), 3.35-3.39 (m, 1 H), 2.71-284 (m, 1 H), 2.50-265 (m, 1 H),

2.13-2.38 (m, 1 H), 1.77-1.96 (m, 1 H), 1.68 (s, 1 H), 1.64 (s, 2 H), 1.47 (s, 3 H), 1.35 - 1.44 (m, 1 H), 1.02 (t, 1 H), 0.94 (t, 2 H).

Step 2. Synthesis of (6S, 7aS) -6-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo [1,2-c1oxazol5 (3H) -one (C33) and (6R, 7aS) -6-ethyl-6 -fluoro-3,3-dimethyltetrahydropyrrolo [1,2-doxazol5 (3H) -one (C34). To a solution of compound C32 (0.80 g, 4.4 mmol) in 5 ml of THF, LDA (2 M, 2.8 ml, 5.6 mmol) was added at about -78 ° C. The reaction mixture was stirred for about 30 minutes, then treated with a solution of N-fluorobis (benzenesulfonyl) measure (NFSI) (1.65 g, 5.3 mmol) in 10 mL of THF. The reaction mixture was maintained for about 10 minutes at about -78 ° C, then heated at about 25 ° C for about 1 h. The reaction was quenched by the addition to EtOAc (10 ml) and water (10 ml). The EtOAc was separated, and the aqueous phase was extracted with additional EtOAc (50 mL x 2). The combined extracts of

-110 EtOAc washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was dissolved in DCM (20 ml) and filtered. The filtrate was concentrated, and the residue was separated by column chromatography to obtain the title compounds C33 (Yield; 180 mg, 20%) and C34 (Yield; 403 mg, 45%):

C33: ¹H NMR (400 MHz, CDCI₃) δ 4.17 (dd, 1 H), 3.84 - 3.95 (m, 1 H), 3.47 (dd, 1 H),

2.54 (ddd, 1 H), 1.95-2.11 (m, 2 H), 1.78 - 1.95 (m, 1 H), 1.72 (s, 3 H), 1.49 (s, 3 H), 1.07 (t, 3H) .

C34: ¹H NMR (400 MHz, CDCI₃) δ 4.29 - 4.40 (m, 1 H), 4.17 (dd, 1 H), 3.34 - 3.43 (m, 1 H), 2.42 (ddd, 1 H), 1.98 - 2.11 (m, 1 H), 1.76 - 1.83 (m, 1 H), 1.71 (ddd, 1 H), 1.65 (s, 3 H), 1.53 (s, 3 H), 1.01 (t, 3 H).

Stage 3; Synthesis of (3S, 5S) -3-ethyl-3-fluoro-5- (h¡drox¡met¡l) pyrrol¡din-2-one (L7),

A solution of compound C33 (180 mg, 0.9 mmol) in MeOH (5 mL) was treated with 4-toluenesulfonic acid (23 mg, 135 pmol). The resulting mixture was stirred at about 70 ° C for about 4 h. The mixture was concentrated in vacuo to obtain the title compound L7. Yield: 150 mg (100%).¹H NMR (400 MHz, CDCI₃) δ

3.75 (dd, 1 H), 3.69 (dd, 1 H), 3.56 (dd, 1 H), 2.31 - 2.44 (m, 1 H), 1.96 - 2.12 (m, 2 H),

1.68-1.85 (m, 1 H), 1.03 (t, 3 H).

Synthesis of (S) -3,3-difluoro-5- (hydroxymethyl) prolrolin-2-one (L6)

OR

HO

This compound was prepared in the same manner as compound L7, substituting NFSI for bromoethane in Step 1. ¹H NMR (400 MHz, CDCI₃) δ 4.07-418 (m, 1 H),

3.78 - 3.92 (m, 1 H), 2.72 - 2.83 (m, 1 H), 2.04 - 2.18 (m, 1 H).

Synthesis of (3R₁5S) -3-ethyl-3-fluoro-5- (hydroxymethyl) pyrrole-2-one (L8).

HO

OR

This compound was prepared in the same manner as compound L7, substituting compound C34 for compound C33 in Step 3. ¹H NMR (400 MHz, CDCI₃) δ

-1113.90 - 4.01 (m, 1 Η), 3.81 (dd, 1 Η), 3.46 (dd, 1 Η), 2.29 - 2.47 (m, 1 Η), 2.00 - 2.11 (m, 1 Η), 1.83 - 2.00 (m, 1 Η), 1.64 - 1.83 (m, 1 Η), 1.02 (t, 3 Η).

Synthesis of (3R, 5S) -3-fluoro-5- (hydroxymethyl) -3-methylpyrrolidin-2-one (L9) and (3S, 5S) -3fluoro-5- (hydroxymethyl) -3-methylpyrrolidine -2-one (L10),

<img file="CU20160149A7_D0065.tif" />

These compounds were prepared in the same manner as compounds L7 and L8, replacing iodomethane with bromoethane in Stage 1, and then the diastereomeric products were separated by chromatography before Stage 2. L9. ¹H NMR (400 MHz, CDCI₃) δ 3.77 - 3.83 (m, 1 H), 3.69 - 3.77 (m, 1 H), 3.53 - 3.62 (m, 1 H),

2.42 - 2.60 (m, 2 H), 1.53 - 1.64 (m, 3 H).

L10: ¹H NMR (400 MHz, CDCl₃) δ 3.73 - 3.80 (m, 1 H), 3.70 (td, 1 H), 3.55 - 3.63 (m, 1 H), 2.26 - 2.40 (m, 1 H), 2.07 - 2.22 (m, 1 H), 1.59 (d, 3 H).

Synthesis of (3S, 5S) -3 - ((benzyloxy) methyl) -3-fluoro-5- (hydroxymethyl) pyrrolidin-2-one (L17) and (3R, 5S) -3 - ((benzyloxy ) methyl) -3-fluoro-5- (hydroxymetii) pyrroiidin-2-one (L18).

<img file="CU20160149A7_D0066.tif" />

These compounds were prepared in the same manner as compounds L7 and L8, substituting NFSi for bromoethane in Stage 1, and benzyloxymethyl chloride (CAS 3587-60-8) with NFSI in Stage 2, and then diastereomeric products were separated. by chromatography The individual diastereomers then underwent Step 3. L17:¹H NMR (400 MHz, CDCI₃) δ 7.27 - 7.42 (m, 5 H), 6.40 6.55 (m, 1 H), 4.60 (s, 2 H), 3.88 - 4.00 (m, 1 H), 3.69 - 3.85 (m, 3 H), 3.46 (dd, 1 H),

2.35 - 2.56 (m, 1 H), 2.16 - 2.33 (m, 1 H). L18:¹H NMR (400 MHz, CDCI₃) δ 7.70 (br. s „1 H), 7.24 - 7.39 (m, 5 H), 4.52 - 4.63 (m, 2 H), 3.63 - 3.86 (m, 4 H), 3.48 (br. s„ 1 H ), 2.61 (d, 1 H), 1.95-2.13 (m, 1 H).

-112 Synthesis of ÍklSL (3R, 5S) -3-fluoro-5- (hydroxymethyl) -3- (2-hydroxypropan-2-yl) pyrrolidine-2-one

<img file="CU20160149A7_D0067.tif" />

This compound was prepared in the same manner as compound L7, substituting NFSI for bromoethane in Step 1, and acetone with NFSI in Step 2, ¹H NMR (400 MHz, CDCI₃) δ 3.45 - 3.42 (m, 1 H), 3.27 (s, 1 H), 2.57 - 2.49 (m, 1 H), 1.98 - 1.90 (m, H), 1.86 - 1.83 (m, 3 H), 1.32 -1.31 (m, 3 H).

Synthesis of (5S) -3-hydroxy-5- (hydroxymethyl) -3- (2,2,2-trifluoroethyl) pyrrolidin-2-one (L21),

<img file="CU20160149A7_D0068.tif" />

This compound was prepared in the same manner as compound L7, substituting

1,1,1-trifluoro-2-iodoethane, which was added slowly, by bromoethane in Stage 1, and CAS 104372-31-8 by NFSI in Stage 2. LCMS: R_t= 1,128 min (213.7, MH⁺); 1,258 (213.7, MH⁺).

Synthesis of (5S) -3-fluoro-5- (hydroxymethyl) -3- (2,2,2-trifluoroethyl) pyrrolidin-2-one (L26),

F

<img file="CU20160149A7_D0069.tif" />

This compound was prepared in the same manner as compound L7, substituting (3R, 7aS) -3- (4-methoxyphenyl) tetrahydropyrrolo [1,2-c] oxazol-5 (3H) -one (CAS 170885-05-9 ) by (S) -3,3-dimethitetrahydropyrrolo [1,2-c] oxazol-5 (1H) -one (CAS 99208-71-6), and 1,1,1-trifluoro-2-iodoethane, which was added slowly , by bromoethane in Stage 1. ¹H

-113NMR (400 MHz, CD₃OD) δ 3.57 - 3.53 (m, 1 H), 3.46 - 3.38 (m, 2 H), 2.93 - 2.80 (m, 1 H), 2.70 - 2.35 (m, 2 H), 2.27 - 2.10 (m, 1 H).

Preparation 20: (3S, 5S) -3-fluoro-3- (fluoromethyl) -5- (hydroxylmethyl) pyrrolidin-2-one (L23).

OR.

HN

HO

Step 1. Synthesis of 3,3-d-methyl-5-oxohexahydropyrrolo [1,2-cjoxazol-6-carboxylate of (7aS) -methyl (C35).

To a solution of (S) -3,3-dimethyltetrahydropyrrolo [1,2-c] oxazol-5 (3H) -one (CAS 9920871-6, 7.0 g, 45 mmol) in THF (70 ml), LDA (2.0 M, 56.4 ml, 113 mmol) was added dropwise at about -78 ° C. The reaction mixture was stirred for about 30 min, and then treated with dimethyl carbonate (10.2 g, 113 mmol) in one portion. The mixture was stirred for a further 10 min at about -78 ° C, then heated to about 25 ° C and stirred for about 1 h. Saturated aqueous potassium diacid phosphate was added, and the mixture was extracted with EtOAc. The extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C35. Yield: 6.8 g (71%).¹H NMR (400 MHz, CDCI₃) δ 4.43 - 4.53 (m, 1 H, secondary diastereomer), 4.16 - 4.25 (m, 1 H, primary diastereomer), 4.08 - 4.16 (m, 1 H, both diastereomers), 3.85 (dd, 1 H, primary diastereomer ), 3.81 (s, 3 H, primary diastereomer), 3.79 (s, 3 H, secondary diastereomer), 3.64 (d, 1 H, secondary diastereomer), 3.53 - 3.60 (m, 1

H, primary diastereomer), 3.43 - 3.51 (m, 1 H, secondary diastereomer), 2.49 - 2.57 (m, 1 H, secondary diastereomer), 2.34 - 2.44 (m, 1 H, primary diastereomer), 2.22 - 2.33 (m , 1 H, primary diastereomer), 1.98 (dt, 1 Hm secondary diastereomer),

I. 68 (s, 3 H, secondary diastereomer), 1.67 (s, 3 H, primary diastereomer), 1.48 (s, 3 H, both diastereomers).

Step 2. Synthesis of 6-fluoro-3,3-dimethyl-5-oxohexahydropyrrolo [1,2-cjoxazol-6-carboxylate of (7aS) -methyl (C36).

A solution of compound C35 (6.8 g, 32 mmol) in THF (128 ml) was treated with DBU (5.8 g, 38 mmol). The mixture was stirred for about 15 min at about 25

-114 ° C, then cooled to about 0 ° C and treated with NFSI (12.1 g, 38 mmol). It was kept at about 0 ° C for about 15 min, then heated at about 25 ° C for about 3 h. The mixture was concentrated, and the residue was diluted with EtOAc and washed with 10% K₂CO₃ aqueous. The mixture was separated, and the aqueous layer was extracted with EtOAc. The combined extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C36. Yield: 5.0 g (68%).¹H NMR (400 MHz, CDCI₃) δ 4.37 - 4.33 (m, 1 H), 4.13 - 4.10 (m, 1 H), 3.83 (s, 3 H), 3.51 - 3.43 (m, 1 H),

2.49 - 2.42 (m, 2 H), 1.61 (s, 3 H), 1.46 (s, 3 H).

Step 3. Synthesis of (6R, 7aS) -6-fluoro-6- (hydroxymethyl) -3,3-dimethyltetrahydropyrrolof1,2-cjoxazol-5 (3H) -one (C37) and (6S, 7aS) -6-fluoro-6 - (hydroxymethyl) -3,3-dimethyltetrahydropyrroloH, 2-c1oxazol-5 (3H) -one (C38),

A solution of compound C36 (6.0 g, 26 mmol) in EtOH (100 mL) at about 0 ° C was treated with NaBH₄ (1.7 g, 44 mmol) that was added in one portion. The mixture was stirred at about 0 ° C for about 1.5 h, then treated with 1 M HCI and then concentrated. The residue was purified by chromatography to obtain the title compounds C37 (Yield: 1.8 g, 34%) and C38 (Yield: 400 mg, 8%). C37:¹H NMR (400 MHz, CDCI3) δ 4.19 (dd, 1 H), 3.80 - 4.06 (m, 3 H), 3.46 - 3.54 (m, 1 H), 2.79 (ddd, 1 H), 2.10 (dd, 1 H), 1.97 - 2.08 (m, 1 H), 1.72 (s, 3 H), 1.50 (s, 3 H). C38:¹H NMR (400 MHz, CDCI3) δ 4.36 - 4.45 (m, 1 H), 4.19 (dd, 1 H), 3.93 - 4.04 (m, 1 H), 3.78 - 3.88 (m, 1 H), 3.39 - 3.49 (m, 1 H), 2.49 (dd, 1 H), 2.40 (ddd, 1 H), 1.97 - 2.14 (m, 1 H), 1.67 (s, 3 H), 1.54 (s, 3 H).

Step 4. Synthesis of (6S, 7aS) -6-fluoro-6- (fluoromethyl) -3,3-dimethyltetrahydropyrrolof1,2c1oxazol-5 (3H) -one (C39).

A solution of compound C37 (1.5 g, 7.4 mmol) in CHCI₃ (30 ml) and pyridine (3.0 ml, 37 mmol) was cooled to about -78 ° C and treated with DAST (2.1 ml, 16 mmol). The mixture was heated to about 25 ° C and stirred for about 18 h, and then heated to about 45 ° C for about 2 h. The mixture was cooled to about -78 ° C and quenched by the addition of MeOH. The mixture was heated to about 25 ° C, stirred for about 30 min and concentrated. The residue was purified by chromatography to obtain the title compound C39. Yield: 450 mg (30%).¹H NMR (400 MHz, CDCI₃) δ 4.68-462 (m, 1 H), 4.58 1154.51 (m, 1 H); 4.19 (dd, 1 H), 4.03 - 3.95 (m, 1 H), 3.49 (t, 1 H), 2.84 - 2.79 (m, 1 H),

2.14 - 2.03 (m, 1 H), 1.70 (s, 3 H), 1.52 (s, 3 H).

Step 5. Synthesis of (3S, 5S) -3-fluoro-3- (fluoromethyl) -5- (hydroxymethyl) pyrrolidin-2-one (L23).

To a stirred solution of compound C39 (450 mg, 2.2 mmol) in 50.4 ml of acetonitrile and 5.6 ml of water, 4-toluenesulfonic acid (19 mg, 0.11 mmol) was added. The reaction mixture was stirred at about 25 ° C for about 16 h and then heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L23. Yield: 260 mg (72%).¹H NMR (400 MHz, CDCIs) δ 6.47 (br s, 1 H), 4.73 - 4.65 (m, 1 H), 4.62 - 4.51 (m, 1 H), 3.80 - 3.74 (m, 1 H), 3.58 ( br s, 1 H), 2.72 - 2.62 (m, 1 H), 2.16 - 2.07 (m, 1 H), 2.03 - 2.00 (m, 1 H).

Synthesis of (3R, 5S) -3-fluoro-3- (fluoromethyl) -5- (hydroxylmethyl) pyrrolin-2-one (L24).

<img file="CU20160149A7_D0070.tif" />

This compound was prepared in the same manner as compound L23, substituting C38 for C37 in Step 4.¹H NMR (400 MHz, CD₃OD) δ 4.67 (dd, 1 H), 4.63 (d, 1 H),

3.82 - 3.90 (m, 1 H), 3.62 (dd, 1 H), 3.48 (dd, 1 H), 2.27 - 2.52 (m, 2 H).

Preparation 21: (5S) -5- (hydroxymethyl) -3-methoxypropylene-2-one (L25)

<img file="CU20160149A7_D0071.tif" />

Step 1. Synthesis of (3R, 7aS) -6-hydroxy-3- (4-methoxyphenyl) tetrahydropyrrolo | 1,2-c] oxazol5 (3H) -one (C40), To a solution of (3R, 7aS) -3- (4-methoxyphenyl) tetrahydropyrrolo [1,2c] oxazoi-5 (3H) -one (CAS 170885-05-9, 1.0 g, 4.3 mmol) in THF (20 ml ), was added

LDA (2.0 M, 3.0 ml) at around -78 ° C. The mixture was stirred at about -78 ° C for about 0.5 h, then a solution of (1R) - (-) - 10-116 camphorsulfonyl) oxaziridine (CAS 104372-31-8, 1, 0 g, 4.7 mmol) in THF (10 ml) at about -78 ° C. The mixture was stirred at about -78 ° C for about 10 min and then at about 25 ° C for about 1.5 h. 10 ml of EtOAc and 10 ml of water were added. The mixture was concentrated. The residue was diluted with water and extracted with EtOAc. The EtOAc extracts were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C40. Yield: 450 mg (42%). LCMS: m / z,

250.1 (M + 1), retention time: 0.748 min

Step 2. Synthesis of (3R, 7aS) -6-methox¡-3- (4-methoxyphenyl) tetrah ¡drop¡rrolof1,2-c | oxazol5 (3H) -one (C41), A mixture of compound C40 (468 mg, 1.8 mmol), silver oxide (l) (232 mg, 1.0 mmol) and iodomethane (710 mg, 5.0 mmol) in acetonitrile (20 ml) was stirred at about 25 ° C for about 6 h. Additional silver (I) oxide (464 mg, 2.0 mmol) and iodomethane (710 mg, 5.0 mmol) were added, and after about 18 h, the mixture was filtered and concentrated to obtain the compound of the Title C41 that was used without further purification. Yield: 370 mg (75%). LCMS: m / z, 263.9 (M + 1), retention time: 0.883 min

Step 3. Synthesis of (5S) -5- (hydroxymethyl) -3-methoxypyrrolidin-2-one (L25). A solution of compound C41 (430 mg, 1.6 mmol) in AcOH (8 ml) and water (2 ml) was stirred at about 75 ° C for about 30 min. The mixture was concentrated, MeOH was added, and the resulting mixture was concentrated again. The residue was purified by chromatography to obtain the title compound L25. Yield: 204 mg (86%).¹H NMR (400 MHz, CD₃OD) δ 6.19 (br. S, 1 H) 3.89 - 3.86 (m, 1 H), 3.68 3.65 (m, 2 H), 3.49 - 3.43 (m, 4 H), 2.45 - 2.42 (m, 1 H) , 2.30 - 2.00 (m, 1 H), 1.68 1.64 (m, 1 H).

Preparation 22: (S) -6- (hydroxymethyl) -5-azaspirof2.41heptan-4-one (L27)

<img file="CU20160149A7_D0072.tif" />

Stage 1. Synthesis of (S) -3 ', 3'-dimet¡ld¡hydro-rH-spiro [cyclopropan-1,6^l-pyrrolof1,2c1oxazon-5 '(3'H) -one (C42). A solution of (S) -3,3-dimethyltetrahydropyrrolo [1,2c] oxazol-5 (1H) -one (CAS 99208-71-6, 233 mg, 1.5 mmol) in THF (10 ml) is deal with

LDA (2.0 M, 1.6 ml) at around -78 ° C. A solution of 2,211,3,3,2-dloxatlolane (CAS 1072-53-3, 242 mg, 1.9 mmol) in THF (10 ml) was added at a rate to maintain the internal temperature at around less than -65 ° C. The mixture was stirred at about -78 ° C for about 10 min, then heated to about -20 ° C. The mixture was stirred for about 45 min and gradually heated to about -3 ° C before it was cooled again to about -78 ° C. LDA (2.0 M, 1.95 mmol) was added, and the mixture was stirred for about 10 min at about -78 ° C, then slowly heated to about 25 ° C and held for about 8 h. The mixture was treated with NH₄Semi-saturated aqueous CI and extracted with EtOAc. The EtOAc extracts were washed with NH₄Saturated aqueous CI, dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C42. Yield: 120 mg (44%).¹H NMR (400 MHz, CDCI₃) δ 4.29 - 4.21 (m, 1 H), 4.08 - 4.05 (m, 1 H), 3.43 - 3.38 (m, 1 H), 2.04 - 1.99 (m, 1 H), 1.94 - 1.90 (m, 1 H ), 1.61 (s, 3 H), 1.45 (s, 3 H), 1.19 - 1.14 (m, 1 H), 1.25 - 1.17 (m, 1 H), 1.16 - 1.14 (m, 1 H), 0.95- 0.94 (m, 1 H), 0.93-0.90 (m, 1 H).

Stage 2. Synthesis of (S) -6- (hydroxymethyl) -5-azaspirof2.4lheptan-4-one (L27). To a stirred solution of compound C42 (120 mg, 0.66 mmol) in 4.5 ml of acetonitrile and 0.5 ml of water, 4-toluenesulfonic acid (12 mg, 0.06 mmol) was added. The reaction mixture was heated at about 90 ° C for about 1 h. The reaction mixture was cooled to about 25 ° C and concentrated to obtain the title compound L27 which was used in the next step without further purification. Yield: 105 mg. ¹H NMR (400 MHz, CD₃OD) δ 3.82 - 3.82 (m, 1 H), 3.80 - 3.50 (m, 1 H), 2.33 -2.30 (m, 1 H), 1.98-1.94 (m, 1 H), 1.04-102 (m, 2 H), 0.81-0.80 (m, 2 H).

Preparation 23 (3R, 5S) -3-fluoro-3- (2-fluoroethyl) -5- (hydroxymethyl) pyrrole-2-one (L29)

HO

OR

Step 1. Synthesis of (7aS) -6-allyl-3,3-dimethyltetrahydropyrrolof1,2-c1oxazol-5 (3H) -one (C43).

To a stirred solution of (S) -3,3-dimethyltetrahydropyrrolo [1,2-c] oxazol-5 (1 H) -one (CAS

99208-71-6, 10 g, 64.5 mmol) in THF (160 ml) at -78 ° C, LDA (2 M, 40.3 ml) was added,

-118 and the mixture was stirred for about 0.5 h. Allyl bromide (6.2 mL, 71 mmol) was added, and the mixture was stirred for about 10 min at about -78 ° C, then heated to about 25 ° C and stirred for about 1 h . It was quenched with EtOAc-water (1: 1, 60 ml) and separated. The aqueous phase was extracted with EtOAc, and the combined EtOAc extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to obtain the title compound L29. Yield: 8.85 g (70%).¹H NMR (400 MHz, CDCI₃) δ

5.78 - 5.71 (m, 1 H), 5.14 - 5.02 (m, 2 H), 4.13 - 4.03 (m, 2 H), 3.40 - 3.36 (m, 1 H),

2.90 - 2.72 (m, 1 H), 2.63 - 2.42 (m, 1 H), 2.35 - 2.15 (m, 2 H), 1.95 - 1.87 (m, 1 H),

1.64 (s, 3H), 1.44 (s, 3 H).

Stage 2. Synthesis of (6S, 7aS) -6-al¡l-6-fluoro-3,3-d¡met¡ltetrah¡drop¡rrolof1,2-c] oxazol5 (3H) -ona (C44a), A A stirred solution of L29 (5.0 g, 25.6 mmol) in THF (80 mL) at -78 ° C, LDA (2 M, 16.0 mL) was added. After about 0.5 h, a solution of NFSI (8.89 g, 28.2 mmol) in THF (20 mL) was added, and the mixture was stirred for about 10 min at about -78 ° C . The reaction mixture was heated at about 25 ° C for about 1 h. The mixture was quenched with EtOAc-water (1: 1). The aqueous phase was extracted with EtOAc, and the combined EtOAc extracts were dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C44a. Yield: 1.9 g (35%). The C44b diastereomer was also obtained. Yield: 1.1 g (20%). C44a:¹H NMR (400 MHz, CDCIs) δ 5.78 - 5.68 (m, 1 H), 5.19 - 5.15 (m, 2 H), 4.30 - 4.25 (m, 1 H),

4.11 (dd, 1 H), 3.33 (t, 1 H), 2.72 - 2.65 (m, 1 H), 2.55 - 2.47 (m, 1 H), 2.37 - 2.27 (m, 1 H), 1.85 - 1.70 ( m, 1 H), 1.59 (s, 3 H), 1.48 (s, 3 H). C44b:¹H NMR (400 MHz, CDCI₃) δ 5.85 - 5.76 (m, 1 H), 5.29 - 5.23 (m, 2 H), 4.14 (dd, 1 H), 3.89 - 3.81 (m, 1 H), 3.44 (t, 1 H), 2.75 - 2.67 (m, 1 H), 2.62 - 2.51 (m, 2 H), 2.06 - 1.95 (m, 1 H), 1.54 (s, 3 H), 1.47 (s, 3H).

Stage 3. Synthesis of (6R, 7aS) -6-fiuoro-6- (2-h¡drox¡et¡l) -3,3-dimet¡ltetrah¡dropírrolof1,2jojozolzol-5 (3H) -one (C45) A flow of ozonized oxygen was bubbled through a solution of compound C44a (500 mg, 1.4 mmol) in DCM (20 ml) at about -78 ° C for about 15 min. A flow of argon was passed through the mixture for about 15 min, then the mixture was treated with dimethyl sulphide (5 mL) at about -78 ° C and stirred for about 1 h at about -78 ° C. The reaction mixture was evaporated to dryness, and the residue was dissolved in THF (18 mL)

-119and water (2 mi). NaBH was added₄ (183 mg, 4.6 mmol), and the mixture was stirred at about 25 ° C for about 2 h. The mixture was treated with saturated aqueous NH solution.₄CI and extracted with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, were filtered and concentrated to obtain the title compound C45 as a colorless liquid that was used in the next step without further purification. Yield: 370 mg (71%).¹H NMR (400 MHz, dmso-d₆) δ 4.61 (t, 1 H), 4.11 - 4.08 (m, 1 H), 4.00 - 3.94 (m, 1 H), 3.62 - 3.52 (m, 2 H), 3.47 (t, 1 H), 2.74 - 2.69 (m, 1 H), 2.05 - 1.91 (m, 3 H), 1.56 (s, 3 H), 1.36 (s, 3 H).

Step 4. Synthesis of (6R, 7aS) -6-fluoro-6- (2-fluoroethyl) -3,3-d-methyltetrahydropyrrolo [1,2c1oxazol-5 (3H) -one (C46). To a solution of compound C45 (370 mg, 1.7 mmol) in CHCI₃ (15 ml), pyridine (0.69 ml, 8.5 mmol) was added and then DAST (0.4 ml, 3.07 mmol) at about -78 ° C. The mixture was heated to about 25 ° C and stirred for about 18 h. Then, the mixture was cooled to about -78 ° C and quenched by the slow addition of MeOH. After about 30 min at about -78 ° C, the mixture was heated to about 25 ° C and stirred for about 30 min before it evaporated to dryness. The residue was purified by chromatography to obtain the title compound C46. Yield: 120 mg (32%).¹H NMR (400 MHz, CDCI₃) δ 4.80 - 4.53 (m, 2 H), 4.17 - 4.14 (m, 1 H), 3.96 - 3.91 (m, 1 H), 3.46 (t, 1 H), 2.76 - 2.71 (m, 1 H), 2.34 - 2.19 (m, 2 H), 2.09-1.9 (m, 1 H), 1.68 (s, 3 H), 1.44 (s, 3 H).

Step 5. Synthesis of (3R, 5S) -3-fluoro-3- (2-fluoroethyl) -5- (hydroxymethyl) pyrrolidine-2-one (L29),

To a stirred solution of compound C46 (130 mg, 0.62 mmol) in 5 ml of acetonitrile and 0.5 ml of water, 4-toluenesulfonic acid (11 mg, 0.06 mmol) was added. The reaction mixture was heated at about 90 ° C for about 1 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L29. Yield: 170 mg (83%).¹H NMR (400 MHz, CDCI₃) δ 6.86 (br. s „1 H), 4.52 - 4.96 (m, 2 H), 3.72 - 3.90 (m, 2 H), 3.55 - 3.72 (m, 1 H), 2.53 - 2.73 (m, 1 H ), 2.31 - 2.51 (m, 1 H), 2.05 - 2.31 (m, 2 H).

Preparation 24: (3R, 5S) -5- (hydroxymethyl) -3- (tetrahydro-2H-pyran-4-yl) prolrolin-2-one (L30)

-120HO— &lt;

Stage 1. Synthesis of (6S, 7aS) -6- (4-hdroxytetrahydro-2H-p¡ran-4-¡l) -3,3-d¡met¡ltetrahydropyrrolo-1,2-c] oxazol- 5 (3H) -one (C47). A stirred solution of (S) -3,3dlmethyltetrah¡drop¡rrolo [1,2-c] oxazol-5 (3H) -one (CAS 99208-71-6, 10.0 g, 64 mmol) in THF (200 mi) was cooled to about -78 ° C, and LDA (2M, 80 mL, 160 mmol) was added. The mixture was stirred at about -78 ° C for about 30 min, and then teírahdro-4H-p¡ran-4-one (CAS 29943-42-8, 15 ml, 160 mmol) in THF was added (50 mi) The mixture was heated to about 25 ° C and stirred for about 2 h before the reaction was quenched with EtOAc-water (1: 1). The EtOAc was separated, and the aqueous layer was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C47. Yield: 12 g (74%).¹H NMR (400 MHz, dmso-d₆) δ 4.14 (m, 1 H), 3.97 - 4.07 (m, 3 H), 3.34 - 3.42 (m, 3 H), 2.59 - 2.63 (m, 1 H), 1.99 - 2.05 (m, 2 H), 1.44 - 1.67 (m, 10 H).

Stage_2._Synthesis_of_ (S) -6- (d¡hydro-2H-plran-4 (3H) -lliden) -3,3dimethyltetrahydropyrrolofl, 2-cjoxazol-5 (3H) -one (C48), Triethylamine (38 ml) was added , 274 mmol) to a stirred solution of compound C47 (7.0 g, 27 mmol) in DCM (150 ml). The resulting mixture was cooled to about 0 ° C, and methanesulfonyl chloride (10.6 mL, 137 mmol) was added. The reaction mixture was heated to about 25 ° C and stirred for about 16 h, then diluted with DCM and water. The DCM was separated, and the aqueous layer was extracted with DCM. The combined DCM extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C48. Yield: 1.0 g (16%).¹H NMR (400 MHz, dmso-d₆) δ 5.61 (dd, 1 H), 4.22 - 4.27 (m, 1 H), 4.14 - 4.15 (m, 2 H), 4.05 - 4.08 (dd, 1 H), 3.79 - 3.81 (m, 2 H), 3.40 - 3.45 (m, 1 H), 3.25 (d, 1 H), 2.15-2.20 (m, 2 H), 2.10 (ddd, 1 H), 1.92-2.04 (m, 1 H), 1.65 (s, 3H), 1.45 (s, 3H).

Stage 3, Synthesis of (6R, 7aS) -3,3-dlmethyl-6- (tetrahydro-2H-pyran-4, tetrahydroplrrolofl, 2-cjoxazol-5 (3H) -one (C49). To a stirred solution of compound

C48 (1.1 g, 4.6 mmol) in EtOAc (50 ml) was added platinum dioxide (105 mg, 0.46

-121mmol). The reaction mixture was stirred at about 50 psi of hydrogen at about 25 ° C for about 4 h. The mixture was filtered, and the solids were washed with EtOAc. The filtrate was concentrated, and the residue was purified by chromatography to obtain the title compound C49. Yield: 0.75g (68%)¹H NMR (400 MHz, dmso-d₆) δ 4.14 (m, 1 H), 4.04 - 4.07 (dd, 1 H), 3.96 - 4.00 (m, 2 H), 3.34 - 3.42 (m, 3 H), 2.59 - 2.62 (m, 1 H), 1.98 - 2.05 (m, 2 H), 1.83 - 1.89 (m, 1 H), 1.65 - 1.66 (m, 3 H), 1.44-1.61 (m, 7 H).

Step 4. Synthesis of (3R, 5S) -5- (hydroxylmethyl) -3- (tetrahydro-2H-pyran-4-yl) pyrrolidin-2-one (L30). A solution of compound C49 (300 mg, 1.25 mmol) in acetonitrile (5 mL) and water (0.5 mL) was treated with 4-toluenesulfonic acid (11.9 mg, 0.06 mmol). The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L30. Yield: 225 mg (90%). ¹H NMR (400 MHz, CDCI₃) δ 6.69 (s, 1 H), 3.97 (d, 2 H), 3.65 (m, 2 H), 3.47 - 3.36 (m, 3 H), 3.07 (m, 1 H), 2.48 - 2.43 (m, 1 H), 1.99 - 2.07 (m, 2 H), 1.82 - 1.88 (m, 1 H), 1.63 - 1.66 (m, 1 H), 1.41-1.49 (m, 3 H).

Preparation 25: (3R, 5S) -3- (3-fluorooxetan-3-¡) -5- (hydroxymethyl) pyrrolin-2-one (L32)

OR

To Xo

HO ~&gt;

Stage 1. Synthesis of (6R, 7aS) -6- (3-fluorooxetan-3-yl) -3,3-d-methyltetrahydropyrrolof1,2c1oxazol-5 (3H) -one (C50). DAST (0.41 ml, 2.9 mmol) was added dropwise to a solution of compound C81 (0.51 g, 2.2 mmol) in DCM (20 ml) at about -78 ° C. After about 2 h, the reaction temperature increased to about 0 ° C and was quenched with 50 ml of phosphate buffer at about pH 7 and heated to about 25 ° C. The DCM was separated, and the aqueous layer was extracted twice with DCM. The combined DCM layers were washed with NaHCO₃, brine, dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain a sample of compound C50 (0.47 g), which was contaminated with an olefinic byproduct. To remove this olefin, the sample was dissolved in EtOH (15 mL), treated with Pearlman catalyst (170 mg) and hydrogenated at 40 psi for about 2 h. The mixture was filtered and concentrated. The residue was purified by chromatography to obtain the title compound C50. performance

-1220.14 g (36%) ¹H NMR (400 MHz, CDCI₃) δ 4.93 - 5.09 (m, 2 H) 4.74 - 4.87 (m, 1 H)

4.53 - 4.65 (m, 1 H) 4.16 - 4.25 (m, 1 H) 4.10 - 4.15 (m, 1 H) 3.52 - 3.67 (m, 1 H) 3.47 (t, 1 H) 2.32 (ddd, 1 H) 1.75 (td, 1 H) 1.65 (s, 3 H) 1.48 (s, 3 H). It also occurred in Stage 1 (6S, 7aS) -3,3-d-methyl-6- (oxetan-3-yl) tetrah ¡dropirrolo [1,2-c] oxazol-5 (3H) one (C51) .¹H NMR (400 MHz, CDCI₃) δ 4.93 (dd, 1 H), 4.79 (dd, 1 H), 4.60 - 4.68 (m, 1 H), 4.40 (t, 1 H), 4.13 - 4.22 (m, 1 H), 4.06 - 4.13 ( m, 3 H), 3.39 - 3.47 (m, 1 H), 3.16 3.35 (m, 2 H), 2.37 (ddd, 1 H), 1.60 (s, 3 H), 1.46 - 1.56 (m, 1 H) , 1.44 (s, 3 H).

Step 2. Synthesis of (3R, 5S) -3- (3-fluorooxetan-3-yl) -5- (hydroxymethyl) pyrrolidin-2-one (L32).

Compound C50 (130 mg, 0.56 mmol) was dissolved in 18 ml of acetonitrile and 2 ml of water and treated with 4-toluenesulfonic acid (5 mg, 0.03 mmol). The resulting mixture was stirred at about 25 ° C for about 18 h, with further stirring at about 95 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L32. Yield 68 mg (64%). It was used without further characterization.

Preparation 26: (3R, 5S) -3-fluoro-5- (hydroxymethyl) -3- (methoxymethyl) pyrrolin-2-one (L33)

<img file="CU20160149A7_D0073.tif" />

Stage 1. Synthesis of (6R, 7aS) -6-fluoro-6- (methoxymethyl) -3,3-d-methyltetrah¡drop¡rrolof1,2c1oxazol-5 (3H) -one (C52), Hexamethyldisilazlda was added of lithium (1 M, 1.3 ml) to a solution of compound C37 (180 mg, 0.89 mmol) in THF (6 ml) at about 0 ° C. After about 0 minutes, iodomethane (0.55 mL, 8.8 mmol) was added. The mixture was heated to about 25 ° C and stirred for about 12 h. Additional lithium hexamethyldisilazlda and iodomethane were added, and the mixture was stirred for an additional 12 h. The reaction was then treated with water and EtOAc. The EtOAc was separated, and the aqueous phase was extracted with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C52. Yield: 116 mg (60%).¹H NMR (400 MHz, CDCI₃) δ 4.17 (dd, 1 H), 3.99 (dd, 1 H), 3.64 - 3.78 (m, 2 H), 3.40 - 3.52 (m, 4 H), 2.78 (ddd, 1 H), 1.94 - 2.11 ( m, 1 H), 1.72 (s, 3 H), 1.49 (s, 3 H).

-123 Stage 2. Synthesis of (3R, 5S) -3-fluoro-5- (hydroxymethyl) -3- (methoxymethyl) pyrrolidine-2-one (L33). The compound C52 (116 mg, 0.53 mmol) was dissolved in 18 ml of acetonitrile and 2 ml of water and treated with 4-toluenesulfonic acid (5 mg, 0.03 mmol). The resulting mixture was stirred at about 25 ° C for about 18 h, with further stirring at about 95 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L33. Yield: 89 mg (94%). It was used without further characterization.

Preparation 27: (3R, 5S) -5- (hydroxymethyl) -3- (oxetan-3-1) pyrrolidine-2-one (L34)

HO

Stage 1. Synthesis of (3R, 5S) -5- (hydroxymethyl) -3- (oxetan-3-l) pyrrolin-2-one (L34).

To a stirred solution of compound C51 (130 mg, 0.62 mmol) in 8 ml of acetonitrile and 0.5 ml of water, 4-toluenesulfonic acid (6 mg, 0.03 mmol) was added. The reaction mixture was heated at about 90 ° C for about 6 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L34. Yield: 35 mg (33%).¹H NMR (400 MHz, CDCI₃) δ 6.04 (bs, 1 H), 4.91 (t, 1 H), 4.80 (t, 1 H), 4.69 (t, 1 H),

4.46 (t, 1 H), 3.75 - 3.80 (m, 2 H), 3.42 - 3.47 (m, 1 H), 3.20 - 3.26 (m, 1 H), 2.89 2.96 (m, 1 H), 2.33 - 2.40 (m, 2 H).

Preparation 28: (4R, 5S) -5- (hydroxymethyl) -4-methylpyrrolidin-2-one (L36)

HO

OR

Stage 1. Synthesis of (7R, 7aS) -3.3,7-trimethyltetrahydropyrrolof1,2-cloxazol-5 (3H) -one (C53L

A suspension of cuprous bromide-dimethyl sulfide complex (11.9 g, 57 mmol) in ether (100 ml) was cooled to about -10 ° C, and a solution of methyl lithium (1.6 M) was added slowly , 71.4 mi, 114 mmol). The mixture was then cooled to about -73 ° C, and TMSCi (7.18 mL, 57 mmol) was added slowly. After the addition was completed, the mixture was maintained for about 15 min before

-124 that compound P20 (3.50 g, 23 mmol) in THF (10 mL) be added slowly. The mixture was maintained for an additional 75 min at about -78 ° C before it was heated to about 0 ° C. The mixture was kept at about 0 ° C for about 45 min before it was treated with a mixture of NH₄Saturated aqueous CI and ammonium hydroxide. The ether layer was separated, and the aqueous phase was extracted twice with EtOAc. The combined extracts were dried in MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C53. Yield: 2.27 g (59%).¹H NMR (400 MHz, CDCI₃) δ

4.32 (dt, 1 H), 3.89 (dd, 1 H), 3.66 - 3.77 (m, 1 H), 2.99 (dd, 1 H), 2.42 - 2.56 (m, 1 H),

2.13 (dd, 1 H), 1.65 (s, 3 H), 1.47 (s, 3 H), 1.02 (d, 3 H).

Stage 2. Synthesis of (4R, 5S) -5- (hydroxymethyl) -4-methylpyrrolidin-2-one (L36).

To a stirred solution of compound C53 (1.00 g, 5.9 mmol) in 18 ml of acetonitrile and 2 ml of water, 4-toluenesulfonic acid (8 mg, 0.04 mmol) was added. The reaction mixture was heated at about 95 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L36. Yield: 0.67 g (88%).¹H NMR (400 MHz, CD₃OD) δ 3.53-3.71 (m, 3 H), 2.57-2.74 (m, 1 H), 2.36 (dd, 1 H),

2.10 (dd, 1 H), 1.11 (d, 3 H).

Synthesis of (4S, 5S) -5- (hydroxymethyl) -4-methylpyrrole-2-one (L35).

OR

HO

This compound was prepared in the same manner as compound L36, substituting

2 - (((tert-butyldimethylsilyl) ox¡) methyl) -5-oxo-2,5-dihydro-1 H -pyrrole-1-carboxylate of (S) -butyl (CAS 81658-27-7) by P20 in Step 1 to obtain 2 - (((terbutyldimethylsilyl) oxy) methyl) -3-methyl-5-oxoprrolidine-1-carboxylate of (2S, 3S) -ter-butyl (C78), which was used in stage 2. ¹H NMR (400 MHz, CD₃OD) δ 3.60 (dd, 1 H), 3.48 (dd, 1 H), 3.27 (d, 1 H), 2.55 (dd, 1 H), 2.32 - 2.22 (m, 1 H), 1.95 (dd, 1 H), 1.15 (d, 3

H).

Synthesis of (4S, 5S) -4-ethyl-5- (hydroxymethyl) pyrrolidin-2-one (L46).

-125ΗΟ

This compound was prepared in the same manner as compound L36, replacing CAS 170885-07-1 with P20, and ethylmagnesium bromide with methyl lithium, in Step 1, to obtain (3R, 7S, 7aS) -7-eyl- 3- (4-Methoxyphenyl) tetrahydropyrrolo [1,2-c] oxazol-5 (3H) one (C63), which was used in Step 2. ¹H NMR (400 MHz, CDCI₃) δ 3.66 -3.64 (m, 1 H),

3.42 - 3.35 (m, 2 H), 2.49 - 2.42 (m, 1 H), 2.01 - 1.92 (m, 2 H), 1.54 - 1.47 (m, 1 H),

1.39 -1.32 (m, 1 H), 0.88 - 0.84 (m, 3 H).

Synthesis of (4R, 5S) -4-ethyl-5- (hydroxylmethyl) pyrrolidine-2-one (L47),

<img file="CU20160149A7_D0074.tif" />

This compound was prepared in the same manner as compound L36, substituting ethylmagnesium bromide for methyl lithium in Step 1, to obtain (7R, 7aS) -7-ethyl-3,3d¡met¡ltetrah¡dropirrolo [1,2 -c] oxazol-5 (3H) -one (C54), which was used in Step 2. ¹H NMR (400 MHz, CDCI₃) δ 4.34 (dt, 1 H), 3.90 (dd, 1 H), 3.72 (dd, 1 H), 2.91 (dd, 1 H),

2.31 (dd, 1 H), 2.25 (m, 1 H), 1.65 (s, 3 H), 1.52 (d, 1 H), 1.48 (s, 3 H), 1.27 - 1.38 (m, 1 H), 0.92 (t, 3 H).

Synthesis of (4S, 5S) -5- (hydroxymethyl) -4-vinylpyrrolidine-2-one (L50)

HO

OR

HN

<img file="CU20160149A7_D0075.tif" />

This compound was prepared in the same manner as compound L36, substituting vinyl magnesium bromide for methyl lithium in Step 1, to obtain (7S, 7aS) -3,3dimethyl-7-vinyltetrahydropyl [1,2-c] oxazol-5 (3H) -one (C55), which was used in Stage 2. ¹H NMR (400 MHz, CDCI₃) δ 6.84 (br. s „1 H), 5.88 (ddd, 1 H), 5.18 (d, 1 H), 5.15 (d, 1 H), 3.75 (td, 1 H), 3.63 - 3.71 (m, 1 H), 3.54 - 3.63 (m, 1 H), 3.16 - 3.29 (m, 2 H), 2.33 2.48 (m, 2 H).

Synthesis of (4R, 5S) -5- (h¡drox¡metil) -4-v¡nilp¡rrolid¡n-2-one (L51)

-126 This compound was prepared in the same manner as compound L36, substituting

CAS 170885-07-1 by P20, and vinyl magnesium bromide by methyl lithium, in Stage 1.

¹H NMR (400 MHz, CDCI₃) δ 6.61 (br. s., 1 H), 5.74-591 (m, 1 H), 5.06-5.20 (m, 2

H), 3.80 (d, 1 H), 3.46 - 3.62 (m, 2 H), 2.70 - 2.87 (m, 1 H), 2.56 (dd, 1 H), 2.30 (dd, 2

H).

Synthesis of (4S, 5S) -4-cyclopropyl-5- (hydroxymethyl) pyrrolidine-2-one (L58).

<img file="CU20160149A7_D0076.tif" />

This compound was prepared in the same manner as compound L36, substituting cyclopropylmagnesium bromide for methyl lithium in Step 1, to obtain (7S, 7aS) -7cyclopropyl-3,3-dimethyltetrahydropyrrolo [1,2-c] oxazol-5 (3H) -one (C56), which was used in Stage 2.¹H NMR (400 MHz, CD₃OD) δ 3.80 (d, 2 H), 3.64 (dt, 1 H), 2.23 - 2.42 (m, 2 H), 1.69 - 1.87 (m, 1 H), 0.89 (dtd, 1 H), 0.52 (dd , 2 H), 0.04-0.23 (m, 2 H).

Synthesis of (4R, 5S) -5- (hydroxymethyl) -4-propylpyrrolidin-2-one (L59)

<img file="CU20160149A7_D0077.tif" />

This compound was prepared in the same manner as compound L36, substituting propylmagnesium bromide for methyl lithium in Step 1, to obtain (7R, 7aS) -3,3-dimethyl-7-propyl tetrahydropyrrolo [1,2-c ] oxazol-5 (3H) -one (C57), which was used in Step

2. ¹H NMR (400 MHz, dmso-d₆) δ 7.46 (br. s, 1 H), 4.63 (t, 1 H), 3.44 - 3.36 (m, 3 H),

2.37 - 2.31 (m, 1 H), 2.07 - 2.01 (dd, 1 H), 1.95 - 1.89 (dd, 1 H), 1.48 - 1.41 (m, 1 H),

1.39 - 1.20 (m, 3 H), 0.86 (t, H).

Repair 29: (3R, 4S, 5S) -3-fluoro-5- (hydroxymethyl) -4-methylpyrrolidine-2-one (L37)

Stage 1. Synthesis of (6R, 7S, 7aS) -6-fluoro-3,3,7-trimethyltetrahydropyrrolo [1,2-cloxazol5 (3H) -one (C58). A solution of compound C53 (0.93 g, 5.5 mmol) in THF (22 ml) was cooled to about -78 ° C and treated with LDA (2.0 M, 3.44 ml, 6.88 mmol). The mixture was maintained at about -78 ° C for about 25 min before it was treated with NFSI (2.23 g, 6.8 mmol) in THF (8 ml). After stirring at about -78 ° C for about 5 more minutes, the mixture was heated at about 25 ° C for about 1 h. Ethyl acetate and water were added, and the mixture was concentrated under reduced pressure to remove the THF present. The mixture was extracted twice with EtOAc, and the combined extracts were dried over Na₂SW₄ They were filtered and concentrated. The residue was purified by chromatography to obtain the title compound C58. Yield: 0.56 g (55%).¹H NMR (400 MHz, CDCI₃) δ

4.58-4.77 (m, 1 H), 4.54 (dtd, 1 H), 3.96 (dd, 1 H), 3.68 (dd, 1 H), 2.53 - 2.73 (m, 1 H),

1.66 (s, 3 H), 1.53 (s, 3 H), 1.05 (d, 3 H). ¹⁹F NMR (376 MHz, CDCI3) δ -184.92, (6S, 7S, 7aS) -6-fluoro-3,3,7-trimethyltetrahydropyrrolo [1,2-c] oxazol5 (3H) -one (C59) also occurred . Yield: 0.11 g (11%).¹H NMR (400 MHz, CDCI3) δ 5.25 (dd, 1 H), 3.95 - 4.10 (m, 2 H), 3.71 - 3.82 (m, 1 H), 2.86 - 3.03 (m, 1 H), 1.68 (s , 3 H), 1.49 (s, 3 H), 1.01 (dd, 3 H). ¹⁹F NMR (376 MHz, CDCI₃) δ -202.08.

Stage 2. Synthesis of (3R, 4S, 5S) -3-fluoro-5- (hydroxymethyl) -4-methylpyrrolidine-2-one (L37).

To a stirred solution of compound C58 (590 mg, 3.1 mmol) in 18 ml of acetonitrile and 2 ml of water, 4-toluenesulfonic acid (27 mg, 0.16 mmoi) was added. The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L37. Yield: 451 mg (97%).¹H NMR (400 MHz, CDCI₃) δ 6.94 (br. s „1 H), 4.94 (dd, 1 H), 3.66 - 3.77 (m, 2 H), 3.60 - 3.66 (m, 1 H), 2.93 (t, 1 H), 2.61 - 2.81 (m, 1 H), 1.29 (d, 3 H). ¹⁹F NMR (376 MHz, CDCIs) δ-194.85.

Synthesis of (3S, 4S, 5S) -3-fluoro-5- (hydroxymethyl) -4-methylpyrrolidin-2-one (L38).

This compound was prepared in the same manner as compound L37, substituting compound C59 for compound C58 in Step 2. ¹H NMR (400 MHz, CDCI₃) δ

6.63 (br. S., 1 H), 4.86 (dd, 1 H), 3.72 - 3.83 (m, 2 H), 3.60 - 3.68 (m, 1 H), 2.67 - 2.80 (m, 1 H), 1.96 (br. s., 1 H), 1.10 (dd, 3 H). ¹⁹F NMR (376 MHz, CDCI₃) δ -201.74.

Synthesis of (4R, 5S) -5- (hydroxymethyl) -3,4-dimethylpyrrolidine-2-one (L48).

-128HO

<img file="CU20160149A7_D0078.tif" />

This compound was prepared in the same manner as compound L37, replacing iodomethane with NFSI in Step 1, to obtain (7R, 7aS) -3,3,6,7 tetramethyltetrapyrrolo [1,2-c] oxazol-5 ( 3H) -one (C60), which was used in Stage 2. ¹H NMR (400 MHz, CD₃OD) δ 3.75-3.50 (m, 3 H), 2.70-2.58 (m, 1 H), 2.29-2.15 (m, 1 H), 1.21-105 (superimposed d, 6 H).

Synthesis of (3S, 4S, 5S) -4-et¡l-3-fluorQ-5- (h¡drQX¡til) p¡rrolid¡n-2-Qna (L54).

This compound was prepared in the same manner as compound L37, substituting compound C54 for compound C53 in Step 1, to obtain (6S, 7S, 7aS) -7ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo [1, 2-c] oxazol-5 (3H) -one (C61), which was used in Step 2. ¹H NMR (400 MHz, CDCI₃) δ 7.59 (br. s „1 H), 4.80 (dd, 1 H), 3.69 - 3.83 (m, 2 H), 3.52 - 3.64 (m, 1 H), 3.48 (br. s, 1 H), 2.27 - 2.52 (m, 1 H), 1.57 - 1.73 (m, 1 H),

1.49 (di, 1 H), 1.04 (t, 3 H). ¹⁹F NMR (376 MHz, CDCI3) δ -198.72. It was also produced in Stage 1 (6R, 7S, 7aS) -7-ethyl-6-fluoro-3,3-dimethyltetrahydro-pyrol [1,2-c] oxazol5 (3H) -one (C62).¹H NMR (400 MHz, CD3CN) δ 4.78 (dd, 1 H), 4.40 (di, 1 H), 3.93 (dd, 1 H), 3.56 (dd, 1 H), 2.30 - 2.46 (m, 1 H) , 1.56 (s, 3 H), 1.52 (ddd, 1 H), 1.42 (s, 3 H),

1.35-1.48 (m, 1 H), 0.97 (t, 3 H).

Synthesis of (3R, 4S, 5S) -4-ethyl-3-fluoro-5- (hydroxymethyl) pyrrolin-2-one (L55).

HO

This compound was prepared in the same manner as compound L37, substituting compound C62 for compound C58 in Step 2. ¹H NMR (400 MHz, dmso-d6) δ 8.05 (br. S, 1 H), 4.88 (dd, 1 H), 3.48 - 3.46 (m, 1 H), 3.41 - 3.38 (m, 2 H), 2.32 2.23 (m, 1 H), 1.62 - 1.55 (m, 2 H), 0.95 (t, 3 H). ¹⁹F NMR (376 MHz, CDCI3) δ -189.64. Synthesis of (3R, 4R, 5S) -4-et¡l-3-fluoro-5- (h¡drox¡met¡l) pyrrol¡d¡n-2-one (L57).

HO

-129 This compound was prepared in the same manner as compound L37, substituting compound C63 for compound C53 in Step 1, to obtain (3R, 6R, 7R, 7aS) 7-ethyl-6-fluoro-3- (4 -methox¡-phenyl) tetrahydropyrrolo [1,2-c] oxazol-5 (3H) -one (C64), which was used in Step 2. ¹H NMR (400 MHz, CDCI₃) δ 4.92 (dd, 1 H), 3.83-3.80 (m, 1 H),

3.56-3.48 m, 2 H), 2.17-2.10 (m, 1 H), 1.76-1.70 (m, 1 H), 1.52 - 1.46 (m, 1 H), 0.99 (t, 1 H).

Synthesis of (3S, 4R, 5S) -3-fluoro-5- (hydroxymethyl) -4-methylpyrrolidin-2-one (L90).

<img file="CU20160149A7_D0079.tif" />

This compound was prepared in the same manner as compound L37, substituting compound C78 for compound C53 in Step 1. ¹H NMR (400 MHz, CDCI₃) δ

6.82 (br. S., 1 H), 4.73 (dd, 1 H), 3.87 (dd, 1 H), 3.56 (dd, 1 H), 3.28 - 3.37 (m, 1 H),

2.24-237 (m, 1 H), 1.21 (d, 3 H).

Synthesis of (3S, 4S, 5S) -4-cyclopropyl-3-fluoro-5- (hydroxymethyl) pyrrolidine-2-one (L119).

<img file="CU20160149A7_D0080.tif" />

This compound was prepared in the same manner as compound L37, substituting compound C56 for compound C53 in Step 1, to obtain (6S, 7S, 7aS) -7cyclopropyl-6-fluoro-3,3-dimethyltetrahydropyrrolo [1, 2-c] oxazol-5 (3H) -one (C162), which was used in Step 2.¹H NMR (400 MHz, CD₃OD) δ 4.85 (dd, 1 H), 3.94 (dd, 1 H), 3.70 3.79 (m, 1 H), 3.60 - 3.70 (m, 1 H), 1.74 - 1.94 (m, 1 H), 0.78 - 0.94 (m, 1 H), 0.53 0.70 (m, 2 H), 0.23 - 0.37 (m, 2 H). It also occurred in Stage 1 (6R, 7S, 7aS) -7c-cyclopropyl-6-fluoro-3,3-dimethyltetrahydro-pyrol [1,2-c] oxazol-5 (3H) -one (C163) .¹H NMR (400 MHz, CDCIs) δ 4.91 (d, 1 Η), 4.44 - 4.57 (m, 1 Η), 3.94 - 4.09 (m, 2 H), 1.70 -1.76 (m, 1 H), 1.67 (s , 3 H), 1.54 (s, 3 H), 0.55 - 0.73 (m, 3 H), 0.29 - 0.38 (m, 1 H), 0.17 0.27 (m, 1 H)

Synthesis of (3R, 4S, 5S) -4-cyclopropyl-3-fluoro-5- (hydroxymethyl) pyrrolidin-2-one (L120),

-130HO

<img file="CU20160149A7_D0081.tif" />

This compound was prepared in the same manner as compound L37, substituting compound C163 for compound C58 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 5.13 (dd, 1 H), 3.86 (dd, 1 H), 3.58 - 3.72 (m, 2 H), 1.71 - 1.92 (m, 1 H), 1.08 (dtd, 1 H), 0.51 - 0.70 (m, 2 H), 0.37 (dq, 1 H), 0.14 - 0.26 (m, 1 H).

Preparation 30: (4S, 5S) -4-ethyl-3,3-dfluoro-5- (hydroxymethyl) pyrrolidin-2-one (L40)

HO

Stage 1. Synthesis of (7S, 7aS) -7-ethyl-6,6-difluoro-3,3-dimethyltrahydropyrrolo [1,2c1oxazol-5 (3H) -one (C65). A solution of compound C62 (0.80 g, 4.0 mmol) in THF (30 mL) was treated with LDA (2M, 4.97 mL, 9.94 mmol) slowly at about -78 ° C. The mixture was maintained at about -78 ° C for about 45 min before the addition of a solution of NFSI (1.63 g, 5.17 mmol) in THF (10 mL). The mixture was kept at about -78 ° C for about 15 min after the addition was completed, then heated at about 25 ° C for about 2 h. Water and EtOAc were added, and the EtOAc separated. The aqueous phase was extracted with EtOAc, and the combined EtOAc extracts were washed with water, brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C65. Yield: 350 mg (40%).¹H NMR (400 MHz, dmso-d₆) δ 4.24 (dd, 1 H), 4.09 (dd, 1 H), 3.57 (m, 1 Η), 2.80 - 2.76 (m, 1 H), 1.56 (s, 3 H), 1.53 - 1.38 (m, 2 H), 1.42 (s, 3 H), 0.92 (t, 3 H).

Stage 2. Synthesis of (4S, 5S) -4-ethyl-3,3-difluoro-5- (hydroxymethyl) pyrrolidin-2-one (L40),

To a stirred solution of compound C65 (350 mg, 1.91 mmol) in 14 ml of acetonitrile and 1.6 ml of water, 4-toluenesulfonic acid (18 mg, 0.09 mmol) was added. The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L40. Yield: 260 mg (76%).¹H NMR (400 MHz, CDCI₃) δ 6.59 (br. s, 1 H), 3.78 -1313.75 (m, 2 Η), 3.53 - 3.51 (m, 1 Η), 2.65 - 2.52 (m 1 Η), 1.89 (br. s, 1 H) , 1.79 - 1.69 (m, 1 H), 1.52 - 1.45 (m, 1 H), 1.08 (t, 3 H).

Synthesis of (4S, 5S) -3,3-difluoro-5- (hydroxymethyl) -4-methylpyrrolidin-2-one (L39)

<img file="CU20160149A7_D0082.tif" />

This compound was prepared in the same manner as compound L40, substituting compound C58 for compound C62 in Step 1. ¹H NMR (400 MHz, CDCI₃) δ

3.76 - 3.48 (m, 2 H), 3.29 - 2.71 (m, 1 H), 2.69 - 2.60 (m, 1 H), 1.18 - 1.06 (d, 3 H). Synthesis of (3R, 4S, 5S) -3 - ((benzylox) methyl) -3-fluoro-5- (hydroxymethyl) -4-methylpyrrolidine-2one (L41)

<img file="CU20160149A7_D0083.tif" />

This compound was prepared in the same manner as compound L40, substituting compound C58 for compound C62, and benzyloxymethyl chloride (CAS 3587-60-8) with NFSI, in Step 1 to obtain (6R, 7S, 7aS) -6 - ((benzyloxy) methyl) -6-fluoro-3,3,7-trimethyltetrahydro-pyrrolo [1,2-c] oxazol-5 (3H) -one (C66), which was used in Step 2. ¹H NMR (400 MHz, CDCI3) δ 7.21 - 7.41 (m, 5 H), 4.57 (d, 2 H), 3.47 - 3.86 (m, 5 H), 2.71 - 2.93 (m, 1 H), 1.04 (d , 3 H). It also occurred in Stage 1 (6S, 7S, 7aS) -6 ((benzyloxy) methyl) -6-fluoro-3,3,7-trimethyltetrahydropyrrolo [1,2-c] oxazol-5 (3H) -one ( C67).¹H NMR (400 MHz, CDCI3) δ 7.28-7.40 (m, 5 H), 4.68 (d, 1 H), 4.53 (d, 1 H), 4.45 4.51 (m, 1 H), 3.95 (dd, 1 H ), 3.88 (dd, 1 H), 3.59 - 3.74 (m, 2 H), 2.72 - 2.85 (m, 1 H),

1.61 (s, 3 H), 1.51 (s, 3 H), 0.99 (d, 3 H)

Synthesis of (3S, 4S, 5S) -3 - ((benzyloxy) methyl) -3-fluoro-5- (hydroxymethyl) -4-methylpyrrolidine-2one (L42).

OR

<img file="CU20160149A7_D0084.tif" />

This compound was prepared in the same manner as compound L40, substituting compound C67 for compound C65 in Step 2. ¹H NMR (400 MHz, CDCI₃) δ

-1327.28 - 7.45 (m, 5 Η), 6.85 (br. S., 1 H), 4.60 (s, 2 H), 3.87 - 3.99 (m, 1 H), 3.65 - 3.86 (m, 3 H), 3.44 (dd, 1 H), 2.32 - 2.55 (m, 1 H), 2.20 - 2.33 (m, 1 H).

Synthesis of (3R, 4S, 5S) -3-fluoro-5- (hydroxymethyl) -3,4-dimethylpyrrolidin-2-one (L44)

<img file="CU20160149A7_D0085.tif" />

This compound was prepared in the same manner as compound L40, substituting compound C60 for compound C62 in Step 1, to obtain (6R, 7S, 7aS) -6fluoro-3,3,6,7-tetramethyltetrahydropyrrolo [1, 2-c] oxazol-5 (3H) -one (C68), which was used in Step 2.¹H NMR (400 MHz, CD₃OD) δ 4.90-4.78 (m, 2 H), 3.74-3.59 (m, 1 H), 2.81-2.66 (m, 1 H), 1.42 (dd, 3 H), (1.04 (d, 3 H). It also occurred in Stage 1 (6S, 7S, 7aS) -6-fluoro-3,3,6,7-tetramethyltetrahydro-pyrrolo [1,2-c] oxazol-5 (3H) -one (C69). of (3S, 4S, 5S) -3-fluoro-5- (hydroxymethyl) -3,4-dimethylpyrrolidin-2-one (L45)

<img file="CU20160149A7_D0086.tif" />

This compound was prepared in the same manner as compound L40, substituting compound C69 for compound C65 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ

3.59 - 3.56 (m, 2 H), 3.46 - 3.44 (m, 1 H), 2.41 - 2.22 (m, 1 H), 1.48 - 1.39 (m, 3 H),

1.10-1.01 (m, 3 H).

Preparation 31 (4S, 5S) -4 - ((benzyloxy) methyl) -5- (hydroxymethyl) pyrrolidin-2-one (L43)

<img file="CU20160149A7_D0087.tif" />

Stage 1. Synthesis of (3R, 7R, 7aS) -3- (4-methoxyphenyl) -7- (2-methylprop-1-en-1-1) tetrahydropyrrolofl, 2-cjoxazol-5 (3H) -one ( C70), To a solution of cuprous bromide and dimethyl sulfide (6.24 g, 30.2 mmol) in THF (120 ml) was added slowly 2-methyl-1-propenyl magnesium bromide (0.5 M, 121 60.5 mmol) at about -15 ° C. After about 15 min, the mixture was cooled to about -78 ° C. A CAS solution

170885-07-1 (1.4 g, 6.0 mmol) and TMSCI (1.3 g, 12.1 mmol) in THF (25 mL) was added

-133 for about 15 min. After about 1 h, NH was added₄Aqueous CI to the mixture and heated to about 25 ° C. Ethyl acetate was added, and the EtOAc separated, dried over Na₂SW₄, was filtered and concentrated. The residue was purified by chromatography to obtain the title compound C70. Yield: 1.1 g (64.0%).¹H NMR (400 MHz, dmso-d₆) δ 7.30 (d, 2 H), 6.92 (d, 2 H), 6.05 (s, 1 H), 5.27 (dt, 1 H),

4.13 (dd, 1 H), 3.87 - 3.94 (m, 1 H), 3.74 (s, 3 H), 3.59 - 3.65 (m, 1 H), 3.15 - 3.25 (m, 1 H), 2.55 - 2.65 ( m, 1 H), 2.46-252 (s, 1 H), 1.67 (d, 3 H), 1.61 (d, 3 H).

Step 2. Synthesis of (3R, 7S, 7aS) -7- (hydroxymethyl) -3- (4-methoxyphenyl) tetrahydropyrrolo [1,2-cjoxazol-5 (3H) -one (C71). A solution of compound C70 (1.1 g, 3.8 mmol) in DCM (20 ml) was treated with ozone at about -78 ° C. Once there was excess ozone, methyl sulfide (5 ml) was added slowly. The mixture was stirred at about -78 ° C for about 1 hour before it evaporated to dryness. The residue was dissolved in 9 ml of THF and 1 ml of water and treated with NaBH₄ (307 mg, 7.6 mmol). The mixture was stirred for about 2 h at about 25 ° C before it was treated with NH₄Aqueous OI and EtOAc. The EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C71. Yield: 460 mg (46%).¹H NMR (400 MHz, dmsod₆) δ 7.29 (d, 2 H), 6.93 (d, 2 H), 6.03 (s, 1 H), 4.87 (t, 1 H), 4.15 (dd, 1 H), 3.89 - 3.97 (m, 1 H ), 3.75 (s, 3 H), 3.40 - 3.55 (m, 3 H), 2.39 - 2.55 (m, 3 H).

Step 3. Synthesis of (4S, 5S) -4 - ((benzyloxy) methyl) -5- (hydroxymethyl) pyrrolidine-2-one (L43).

A solution of compound C71 (220 mg, 0.84 mmol) in DMF (4.2 ml) was cooled to about 0 ° C and treated with sodium hydride (60%, 40 mg, 1.0 mmol) and then with (bromomethyl) benzene (0.11 ml, 0.92 mmol). The mixture was maintained for about 1 h at about 0 ° C before it was diluted with water. The mixture was extracted with EtOAc. The extracts were dried in Na₂SW₄, filtered and concentrated. The residue was treated with 4-toluenesulfonic acid in acetonitrile and water to obtain the title compound L43. Yield: 100 mg (51%).¹H NMR (400 MHz, dmso-d₆) δ 7.52 (s, 1 H), 7.26 - 7.39 (m, 5 H), 4.77 (t, 1 H), 4.48 (s, 2 H), 3.35 3.46 (m, 3 H), 3.26 - 3.35 (m , 2 H), 2.33 - 2.42 (m, 1 H), 2.24 - 2.33 (m, 1 H), 1.85 1.95 (m, 1 H).

Preparation 32: (4S, 5S) -4- (fluoromethyl) -5- (hydroxymethyl) prolrolin-2-one (L49)

-134 Stage 1. Synthesis of (3R, 7S, 7aS) -7- (fluoromethyl) -3- (4-methoxyphenyl) tetrah, drop it [1,2doxazol-5 (3H) -one (C72) . A solution of compound C71 (460 mg, 1.75 mmol) and 2,6-lutidine (468 mg, 4.37 mmol) in DCM at about 0 ° C was treated with DAST (563 mg,

3.5 mmol). The mixture was stirred at about 25 ° C for about 5 h before it was quenched with NaHCO₃ saturated aqueous and extracted with DCM. The combined DCM extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C72. Yield: 410 mg (88%). LCMS: m / z, 265.3 (M + 1), retention time; 1,602 min.

Step 2. Synthesis of (4S, 5S) -4- (fluoromethyl) -5- (hydroxymethyl) pyrrolidine-2-one (L49). To a stirred solution of compound C71 (100 mg, 0.38 mmol) in 9 ml of acetonitrile and 1 ml of water, 4-toluenesulfonic acid (3 mg, 0.02 mmol) was added. The reaction mixture was heated to about 90 ° C until the solvent evaporated. Additional acetonitrile and water were added, and the operation was repeated several more times. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L49. Yield: 50 mg (90%).¹H NMR (400 MHz, CD₃OD) δ 4.53 - 4.51 (m, 1 H), 4.41 4.40 (m, 1 H), 3.66 - 3.53 (m, 3 H), 2.65 - 2.54 (m, 2 H), 2.21 - 2.16 (m, 1 H ). Preparation 33: (3S, 4S, 5S) -4- (fluoromethyl) -5- (hydroxymethyl) -3-methylpyrrolidin-2-one (L52)

OR

HO

Step 1. Synthesis of (3R, 7S, 7aS) -7- (fluoromethyl) -3- (4-methoxyphenyl) -6-methyltetrahydropyrrolof 1,2-c | oxazol-5 (3H) -one (C73). To a solution of compound C73 (160 mg, 0.61 mmol) in THF (3 ml) at about -78 ° C, LDA (2 M, 0.38 ml) was added. The mixture was stirred for about 0.5 h before iodomethane (107 mg, 0.76 mmol) was added. The mixture was maintained for about 10 min at about -78 ° C before it was heated to about 25 ° C and stirred for about 1 h. EtOAc and water were added, and the mixture was extracted with EtOAc. The combined extracts

-135 EtOAc dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C73. Yield: 140 mg (82%). LCMS: m / z, 279 (M + 1), retention time: 1,244 min

Stage 2. Synthesis of (3S, 4S, 5S) -4- (fluoromethyl) -5- (hydroxymethyl) -3-methylpyrrolidine-2-one (L52). A solution of compound C73 (140 mg, 0.5 mmol) in 6.5 ml of AcOH and 3.5 ml of water was heated at about 90 ° C for about 40 min before it evaporated to dryness. The residue was dissolved in 25 ml of MeOH and concentrated. The residue was purified by chromatography to obtain the title compound L52. Yield: 70 mg (87%).¹H NMR (400 MHz, CD₃OD) δ 4.62 - 4.51 (d, 2 H), 3.71 3.68 (m, 1 H), 3.54 (m, 2 H), 2.41 -2.39 (m, 1 H), 2.23-2.10 (m, 1 H), 1.25 (s, 3 H).

Preparation 34: (3R, 4R, 5R) -3-fluoro-5- (hydroxymethyl) -4-methylpyrrolin-2-one (L53)

<img file="CU20160149A7_D0088.tif" />

Step 1. Synthesis of (7aR) -3,3-dimethyl-6- (phenylslanyl) tetrahydropyroloi1,2-cjoxazol5 (3H) -one (C74). LDA (2M, 41.9 ml) was added to a solution of (R) -3,3-dimethyltetrahydropyrrolo [1,2-c] oxazol-5 (1H) -one (CAS 103630-36-0, 10 g , 64.4 mmol) in THF (130 ml) at about -78 ° C. After about 30 min, diphenyl diselenide (24.13 g, 77.3 mmol) in THF (125 ml) was added. The mixture was kept at about 78 ° C for about 30 min before it was heated at about 25 ° C for about 1 h. Ethyl acetate and water were added, and the mixture was partially concentrated before it was extracted with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C74. Yield: 12.0 g (60%).¹H NMR (400 MHz, CDCI₃) δ 7.72 - 7.64 (m, 2 H), 7.38 7.27 (m, 3 H), 4.27 (dd, 1 H), 4.12 - 4.07 (m, 1 H), 3.98 - 3.92 (m, 2 H), 3.72 - 3.64 (m, 1 H), 3.31 (t, 1 H), 3.13 (t, 1 H), 2.59 - 2.53 (m, 1 H), 2.33 (dd, 2 H), 1.84 - 1.75 (m , 1 H), 1.62 and 1.56 (s, 3 H), 1.59 (s, 3 H), 1.44 and 1.28 (s, 3 H).

Stage 2. Synthesis of (R) -3,3-d¡met¡l-1,7a-dihydropyrrolof1,2-c1oxazol-5 (3H) -one (C75).

A solution of compound C74 (12.0 g, 38.7 mmol) in DCM (150 ml) and pyridine (6.8 ml) at about 0 ° C was treated with 30% hydrogen peroxide solution (17, 86 ml, 128 mmol). The mixture was kept at about 0 ° C for about 30 min before it was slowly heated to about 25 ° C. After about -136 of 3 h, the mixture was diluted with DCM (100 ml) and washed with saturated aqueous NaHCO solution.₃. The DCM extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C75. Yield: 4.0 g (68%).¹H NMR (400 MHz, CDCl₃) δ 7.06 (dd, 1 H), 6.09 (dd, 1 H), 4.66 - 4.62 (m, 1 H), 4.12 (dd, 1 H), 3.33 (dd, 1 H), 1.67 (s, 3 H ), 1.55 (s, 3 H).

Step 3. Synthesis of (7S, 7aR) -3,3,7-trimethyltetrahydropyrrolof1,2-c] oxazol-5 (3H) -one

ÍCZ6L

Methyl lithium (1.6 M, 34.7 ml) was added to a suspension of cuprous bromide-dimethylsulfide complex (5.7g, 27.8 mmol) in diethyl ether (40 ml) at about -10 ° C. After the addition was completed, the solution was cooled to about -78 ° C. After about 10 min, TMSCl (3.5 ml, 27.7 mmol), and then a solution of compound C75 (1.7 g, 11.1 mmol) in THF (28 ml) was added. The mixture was stirred at about -78 ° C for about 2 h. It was then heated at about 20 ° C for about 1 h. A mixture of NH was added₄Aqueous CI and ammonium hydroxide with stirring, then the mixture was diluted with EtOAc. The EtOAc was separated, and the aqueous phase was extracted with EtOAc. The combined EtOAc extracts were washed with water, brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C76. Yield: 1.75 g (93%).¹H NMR (400 MHz, CDCI₃) δ 4.33-4.28 (m, 1 H), 3.86 (dd, 1 H), 3.71 (t, 1 H), 2.97 (dd, 1 H), 2.50 - 2.43 (m, 1 H), 2.11 (d, 1 H), 1.63 (s, 3 H), 1.45 (s, 3H), 1.01 (d, 3H).

Stage 4. Synthesis of (6R, 7R.7aR) -6-fluoro-3,3,7-tr¡met¡ltetrah¡drop¡rrolof1,2-cjoxazol5 (3H) -one (C77), LDA (1 , 8 M, 7.03 ml) to a solution at -78 ° C of compound C76 (1.427 g, 8.4 mmol) in THF (27 ml). After about 1 h, a solution of NFSI (3.43 g, 10.5 mmol) in THF (8 ml) was added. After about 5 min, the mixture was heated to about 25 ° C. After about 3 h, EtOAc and water were added, and the mixture was partially concentrated before it was extracted with EtOAc. The combined EtOAc extracts were dried over MgSO4, filtered and concentrated. The residue was dissolved in DCM and filtered. The filtrate was concentrated, and the residue was purified by chromatography to obtain the title compound C77. Yield: 282 mg (18%).¹H NMR (400 MHz, CD₃CN) δ

-1375.27 (dd, 1 Η), 3.99 - 4.08 (m, 1 Η), 3.95 (dd, 1 Η), 3.72 (t, 1 Η), 2.94 (quind, 1 Η), 1.58 (s, 3H), 1.39 (s, 3H), 0.90 (dd, 3 H).

Stage 5, Synthesis of (3R, 4R, 5R) -3-fluoro-5- (hydroxymethyl) -4-methylpyrrolidin-2-one (L53),

To a stirred solution of compound C77 (280 mg, 1.5 mmol) in 9 ml of acetonitrile and 1 ml of water, 4-toluenesulfonic acid (15 mg 0.07 mmol) was added. The reaction mixture was heated at about 90 ° C for about 1.5 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L53. Yield: 169 mg (77%).¹H NMR (400 MHz, CD₃CN) δ 6.56 (br. S, 1 H), 4.83 (dd, 1 H), 3.52-3.67 (m, 2 H),

3.37 - 3.50 (m, 1 H), 2.83 - 2.94 (m, 1 H), 2.63 - 2.80 (m, 1 H), 0.98 (dd, 3 H).

Preparation 35: (3S, 4S, 5S) -4-ethyl-d5-3-fluoro-5- (hydroxymethyl) pyrrolidin-2-one (L56).

<img file="CU20160149A7_D0089.tif" />

Stage 1, Synthesis of (7R, 7aS) -7-et¡l-ds-3,3-dimethltetrah ¡drop¡rrolof1,2-c1oxazol-5 (3H) onea (C79). A solution of perdeuteroethylmagnesium bromide was prepared from 11.06 g (97 mmol) of ethyl-d5 bromide and magnesium metal (2.73 g, 112 mmol) in 80 ml of

THF. A portion of this solution (43.5 ml) was added to a suspension of cuprous bromide-dimethyl sulphide complex (6.78 g, 32.6 mmol) in THF (40 ml) at about -10 ° C. The mixture was stirred at about -10 ° C for about 10 min before it cooled to about -78 ° C. Chlorotrimethyl siano (3.55 g, 32.6 mmol) was added. After about 15 min, compound P20 (2.0 g,

13.1 mmol) in THF (20 ml). The mixture was kept at about -78 ° C for about 30 min before it was heated at about 25 ° C for about 18 h. A mixture of NH was added₄Aqueous CI and ammonium hydroxide with stirring, then the mixture was diluted with EtOAc and filtered. The EtOAc was separated, and the aqueous phase was extracted with EtOAc. The combined EtOAc extracts were washed with NaHCO₃ and brine, dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C79. Yield: 850 mg (35%).¹H NMR (400 MHz, CDCI₃) δ 4.34 (dt, 1 H), 3.90 (dd, 1 H), 3.68 - 3.75 (m,

H), 2.91 (dd, 1 H), 2.31 (dd, 1 H), 2.24 (t, 1 H), 1.65 (s, 3 H), 1.48 (s, 3 H).

Stage 2. Synthesis of (6S, 7S, 7aS) -7-ethyl-6-fluoro-3_l3-dimethyltetrahyrirrolo [1,2c1oxazol-5 (3H) -one (C80). A solution of compound C79 (512 mg, 2.7 mmol) in 2-138 methylTHF (12.5 mL) was treated at about -78 ° C with lithium hexamethyldlsilazide (1 M, 3.0 mL), and the mixture it was maintained for about 45 min at about -78 ° C before it was added to an NSFI solution at about -78 ° C (1.12 g,

3.54 mmol) in 2-methylTHF (12.5 ml). The mixture was kept at about -78 ° C for about 30 min, then water (10 ml) and EtOAc (10 ml) were added. The EtOAc was separated, and the aqueous phase was extracted with EtOAc (10 mL). The combined EtOAc extracts were washed with sodium iodide solution, sodium thiosulfate solution, NaOH solution, brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C80. Performance; 94 mg (17%).¹H NMR (400 MHz, CD₃CN) δ

5.26 (dd, 1 H), 3.95 - 4.08 (m, 2 H), 3.61 - 3.71 (m, 1 H), 2.62 - 2.75 (m, 1 H), 1.58 (s, 3 H), 1.40 (s, 3 H).

Step 3. Synthesis of (3S, 4S, 5S) -4-ethyl-ds-3-fluoro-5- (hydroxymethyl) pyrrolidin-2-one (L56). To a stirred solution of compound C80 (94 mg, 0.46 mmol) in 18 ml of acetonitrile and 2 ml of water, 4-toluenesulfonic acid (4 mg, 0.02 mmol) was added. The reaction mixture was heated at about 90 ° C for about 4 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L56. Yield: 51 mg (67%). ¹H NMR (400 MHz, CD₃CN) δ 6.76 (br. S., 1 H), 4.73 (dd, 1 H), 3.57-3.67 (m, 2 H),

3.32 - 3.42 (m, 1 H), 2.85 (t, 1 H), 2.40 (dt, 1 H).

Preparation 36: (4R, 5S) -5- (hydroxymethyl) -4- (methoxymethyl) pyrrolidin-2-one (L60)

<img file="CU20160149A7_D0090.tif" />

Stage 1. Synthesis of (7R, 7aS) -7- (hydroxymethyl) -3,3-d-methyltetrahydropyrrolof1,2-cjoxazol5 (3H) -one (C82). A flow of ozonized oxygen was bubbled through a solution of compound C55 (1.95 g, 10.8 mmol) in DCM (49 mL) and MeOH (16 mL) at about -78 ° C for about 2 h. Dimethyl sulfide (10 ml) was added at around -78 ° C and then NaBH₄ (2.44 g, 64.6 mmol) at the same temperature.

After about 30 min, the reaction was heated to about 0 ° C and stirred for about 2 h. Ethyl acetate was added, and the mixture was washed with water, then with brine. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain

-139the compound of title C82. Yield: 1.2 g (60%).¹H NMR (400 MHz, CDCI₃) δ

4.40 - 4.34 (m, 1 H), 3.97 (dd, 1 H), 3.86 (dd, 1 H), 3.72 - 3.62 (m, 2 H), 2.94 (dd, 1 H),

2.58-2.53 (m, 1 H), 2.25 (d, 1 H), 1.64 (s, 3 H), 1.45 (s, 3 H).

Step 2. Synthesis of (7R, 7aS) -7- (methoxymethyl) -3,3-d-methyltetrah, dropyrrolof1,2-cjoxazol5 (3H) -one (C83). To a stirred solution of compound C55 (1.4 g, 7.5 mmol) in THF (40 mL), fresh silver (L) oxide (17.48 g, 75.7 mmol) was added and then iodomethane (5.37 g, 37.8 mmol). The mixture was heated at about 70 ° C for about 16 h. The mixture was then cooled to about 25 ° C, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C83. Yield: 1.1 g (73%).¹H NMR (400 MHz, CDCI₃) δ 4.36-4.30 (m, 1 H), 3.92 (dd, 1 H), 3.68 (dd, 1 H), 3.39 - 3.25 (m, 2 H), 3.30 (s, 3 H), 2.93 (dd, 1 HOUR),

2.61 - 2.53 (m, 1 H), 2.22 (dd, 1 H), 1.62 (s, 3 H), 1.46 (s, 3 H).

Step 3. Synthesis of (4R, 5S) -5- (h¡drox¡met¡l) -4- (methoxymethyl) pyrrol¡din-2-one (L60).

To a stirred solution of compound C83 (200 mg, 1.0 mmol) in 18.8 ml of acetonitrile and 2.1 ml of water, 4-toluenesulfonic acid (9 mg, 0.05 mmol) was added. The reaction mixture was heated at reflux for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L60. Yield: 150 mg (93%).¹H NMR (400 MHz, dmso-d₆) δ 3.49-3.34 (m, 5 H), 3.32 (s, 3 H), 3.23 (s, 3 H), 2.73 2.60 (m, 1 H), 2.09-1.95 (m, 2 H).

Preparation 37: (4R, 5S) -3-fluoro-5- (hydroxymethyl) -4- (methoxymethyl) pyrrole-2-one (L61)

Step 1. Synthesis of (7R, 7aS) -6-fluoro-7- (methoxymethyl) -3,3-dimethyltetrahydropyrrolof1,2c] oxazol-5 (3H) -one (C84). A solution of compound C83 (250 mg, 1.3 mmo!) In THF (10 ml) was treated with lithium hexamethyldisilazide (1 M, 2.13 ml) at -78 ° C and held for about 30 min before of the addition of a solution of NFSI (436 mg, 1.4 mmol) in THF (10 ml). The mixture was maintained for about 30 min at about -78 ° C and then heated at about 25 ° C for about 1 h. Water and EtOAc were added, and the phases separated. The EtOAc extracts were washed with sodium iodide solution, sodium thiosulfate solution, NaOH solution, brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C84. Yield: 90 mg (33%).¹H NMR (400 MHz, CDCI₃) δ 4.88 (d, 1 H), 4.51-4.46 (m, 1 H), 3.96 (dd, 1 H), 3.70 (dd, 1 H), 3.49 - 3.44 (m, 2 H), 3.31 (s, 3 H), 2.74 - 2.63

-140 (m, 1 Η), 1.63 (s, 3 Η), 1.46 (s, 3 H). Also produced (7R, 7aS) -6,6-dtfluoro-7 (methoxymethyl) -3,3-dimethyltetrahydro-pyrrolo [1,2-c] oxazol-5 (3H) -one (C85). Yield 45 mg (15%).¹H NMR (400 MHz, CDCI₃) δ 4.24 - 4.19 (m, 1 H), 4.08 (dd, 1 H), 3.79 (dd, 1 H), 3.55 (dd, 1 H), 3.48 (dd, 1 H), 3.30 (s, 3 H ), 2.94 - 2.85 (m, 1 H), 1.65 (s, 3

H), 1.53 (s, 3H).

Step 2. Synthesis of (7R.7aS) -6-fluoro-7- (methoxymethyl) -3,3-dmethyltetrahydropyrrolof1,2c1oxazol-5 (3H) -one (C86). A solution of compound C84 (125 mg, 0.575 mmol) in THF (10 ml) was treated with potassium hexamethyldisilazlda (1 M, 0.115 ml) at about 0 ° C. After about 5 min, the mixture was heated at about 25 ° C for about 2 h. Aqueous sodium diacid phosphate was added, and the mixture was extracted with EtOAc. The combined EtOAc extracts were washed with water, brine, dried over Na₂SW₄, filtered and concentrated to obtain the title compound C86. Yield: 115 mg (92%).¹H NMR (400 MHz, CDCI₃) δ

5.28 (dd, 1 H, diastereomer 1), 4.89 (d, 1 H, diastereomer 2), 4.51-4.47 (m, 1 H, diastereomer 2), 4.07 -4.01 (m, 2 H, dlastereomer 1), 3.96 (dd, 1 H, dlastereomer 2), 3.83 - 3.78 (m, 1 H, diastereomer 1), 3.70 (dd, 1 H, diastereomer 2), 3.57 - 3.53 (m, 1 H, diastereomer 1), 3.49 - 3.44 (m, 2 H, diastereomer 2), 3.47 - 3.43 (m, 1 H, diastereomer 1), 3.31 (s, 3 H, diastereomer 2), 3.30 (s, 3 H, diastereomer 1), 3,043.00 ( m, 1 H, diastereomer 1), 2.74-263 (m, 1 H, diastereomer 2), 1.67 (s, 3 H, diastereomer 1), 1.63 (s, 3 H, diastereomer 2), 1.49 (s, 3 H, diastereomer 1), 1.46 (s, 3 H, diastereomer 2).

Step 3. Synthesis of (4R, 5S) -3-fluoro-5- (hydroxymethyl) -4- (methoxymethyl) pyrrolidine-2-one (L61), To a stirred solution of compound C86 (130 mg, 0.6 mmol) in 10 ml of acetonitrile and 0.6 ml of water, 4-toluenesulfonic acid (6 mg, 0.03 mmol) was added. The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L61. Yield: 80 mg (76%). ¹H NMR (400 MHz, CDCI₃) δ 5.12 (dd, 1 H, diastereomer

I), 4.94 (dd, 1 H, diastereomer 2), 3.85-3.54 (m, 10 H, diastereomers 1 and 2), 3.42 (s, 3 H, diastereomer 1), 3.37 (s, 3 H, diastereomer 2) , 2.95-284 (m, 2 H, diastereomers 1 and 2).

Synthesis of (4R, 5S) -3,3-dfluoro-5- (hydroxymethyl) -4- (methoxymethyl) pyrrolidine-2-one (L63)

-141-

<img file="CU20160149A7_D0091.tif" />

This compound was prepared in the same manner as compound L61, substituting compound C85 for compound C86 in Step 3. ¹H NMR (400 MHz, CDCI₃) δ

3.88 - 3.81 (m, 2 H), 3.75 - 3.71 (m, 1 H), 3.66 - 3.61 (m, 2 H), 3.39 (s, 3 H), 3.05 2.95 (m, 1 H).

Preparation 38: (3S, 4S, 5S) -4-ethyl-5- (hydroxymethyl) -3-methoxypyrrolidin-2-one (L66)

<img file="CU20160149A7_D0092.tif" />

Step 1. Synthesis of (7S, 7aS) -7-ethyl-6-hydroxy-3,3-dimethyltetrahydropyroloi1,2-cjoxazol5 (3H) -one (C87). A solution of compound C54 (1.0 g, 5.5 mmol) in THF (25 mL) was treated with LDA (3.4 mL, 6.8 mmol) at about -78 ° C. The mixture was maintained for about 20 min and then treated with a solution of (1 R) - (-) - (10 camphorsulfonyljoxaziridine (CAS 104372-31-8, 1.50 g, 6.5 mmol) in THF (5 me). After about 30 min, the mixture was heated at about 25 ° C for about 30 min. Methanol (2 ml) was added, and the mixture was concentrated. The residue was purified by chromatography to obtain the title compound C87. Yield: 800 mg (73%). It was used in the next stage without further characterization.

Step 2, Synthesis of (6S, 7S, 7aS) -7-ethyl-6-methoxy-3,3-dimethyltetrahydropyrrolo [1,2c] oxazol-5 (3H) -one (C88), To a stirred solution of compound C87 (800 mg, 4.0 mmol) in THF (50 mL), freshly prepared silver oxide (1) (9.3 g, 40.2 mmol) was added and then iodomethane (1.25 mL, 20, 1 mmol) The mixture was heated at about 75 ° C for about 16 h. The mixture was then cooled to about 25 ° C, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C88. Yield: 180 mg (21%).¹H NMR (400 MHz, CDCI3) δ 4.09 (d, 1 H), 4.04 - 3.96 (m, 2 H), 3.70 - 3.66 (m, 1 H), 3.55 (s, 3 H), 2.52 - 2.50 (m , 1 H), 1.69 - 1.64 (m, 1 H), 1.62 (s, 3 H), 1.48 - 1.41 (m, 1 H), 1.47 (s, 3 H), 0.90 (t, 3 H). There was also (6R, 7S, 7aS) -7-ethyl-6-methox¡-3,3-d¡met¡ltetrah¡dropirrolo [1,2c] oxazol-5 (3H) -one (C89). Yield: 375 mg (44%).¹H NMR (400 MHz, CDCI3) δ

-1424.44 - 4.40 (m, 1 Η), 3.92 - 3.89 (m, 1 Η), 3.66 (s, 1 Η), 3.64 - 3.59 (m, 1 Η), 3.53 (s, 3 Η), 2.17 - 2.12 (m, 1 Η), 1.62 (s, 3 Η), 1.50 - 1.41 (m, 1 Η), 1.48 (s, 3 Η), 1.38 - 1.30 (m, 1 Η), 0.97 (t, 3 Η).

Stage 3. Synthesis of (3S.4S.5S) -4-ethyl-5- (hydroxymethyl) -3-methoxypyrrolidin-2-one (L66).

To a stirred solution of compound C88 (180 mg, 0.8 mmol) in 9 ml of acetonitrile and 1 ml of water, 4-toluenesulfonic acid (7 mg, 0.04 mmol) was added. The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L66. Yield: 75 mg (51%).¹H NMR (400 MHz, CDCI₃) δ 6.09 (br, 1 H), 3.68-3.64 (m, 2 H), 3.61 (s, 3 H), 3.57 (d, 1 H), 3.48 (br. s, 1 H), 2.84 (br. s, 1 H), 2.42 - 2.30 (m, 1 H), 1.64-1.58 (m, 1 H), 1.47 -1.33 (m, 1 H), 0.97 (t, 3 H).

Synthesis of (3R, 4S, 5S) -4-et¡l-5- (h¡drox¡met¡l) -3-methoxypyrrol¡d¡n-2-one (L67).

<img file="CU20160149A7_D0093.tif" />

This compound was prepared in the same manner as compound L66, substituting compound C89 for compound C88 in Step 3. ¹H NMR (400 MHz, CDCI₃) δ

6.10 (br. S, 1 H), 3.75 - 3.70 (m, 2 H), 3.63 (s, 3 H), 3.62 - 3.60 (m, 2 H), 2.35 - 2.27 (m, 1 H), 2.12 ( br. s, 1 H), 1.73-1.64 (m, 1 H), 1.61 - 1.52 (m, 1 H), 1.00 (t, 3 H). Synthesis of (3S, 4S, 5S) -5- (hydroxymethyl) -3-methoxy-4-methylpyrrolidin-2-one (L64).

<img file="CU20160149A7_D0094.tif" />

This compound was prepared in the same manner as compound L66, substituting compound C53 for compound C54 in Step 1 to obtain (7S, 7aS) -6-hydrox-3,3,7-trimethyltetrahydro-pyrrolo [1,2- c] oxazol-5 (3H) -one (C90). The application of Step 2 to compound C90 yielded (6S, 7S, 7aS) -6-methox¡-3,3,7trimethyltetrah ¡dropirroIo [1,2-c] oxazol-5 (3H) -one (C91) and ( 6R, 7S, 7aS) -6-methox¡-3,3,7tr¡metlltetrah¡dropirrolo [1,2-cjoxazol-5 (3H) -one (C92). The application of Step 3 to compound C91 produced the title compound L64. ¹H NMR (400 MHz, CDCI₃) δ 3.65 - 3.62 (m, 4 H), 3.59 (s, 3 H), 3.48 (br. s, 1 H), 2.69 - 2.64 (m, 1 H), 1.01 (d, 3 H).

-143 Synthesis of (3R, 4S, 5S) -5- (hydroxymethyl) -3-methoxy-4-methylpyrrolidin-2-one (L65).

TO ¹

HN Y '⁰

HO-X

This compound was prepared in the same manner as compound L64, substituting compound C92 for compound C91 in Step 3. ¹H NMR (400 MHz, CDCI₃) δ

6.37 (br. S, 1 H), 3.74 - 3.64 (m, 3 H), 3.63 (s, 3 H), 3.58 - 3.55 (m, 1 H), 2.53 -2.47 (m, 1 H), 2.45 ( br. s, 1 H), 1.20 (d, 3 H).

Synthesis of (4S, 5S) -3- (benzyloxy) -4-ethyl-5- (hydroxymethyl) pyrrolidin-2-one (L68).

<img file="CU20160149A7_D0095.tif" />

This compound was prepared in the same manner as compound L66, substituting (bromomethyl) benzene for iodomethane in Step 2 and using the resulting mixture of diastereomers in Step 3. ¹H NMR (400 MHz, CDCI₃) δ 7.39 - 7.26 (m, 5 H, both diastereomers), 6.27 (br. s, 1 H, both diastereomers), 5.15 (d, 1 H, diastereomer 1), 5.01 (d, 1 H, diastereomer 2), 4.71 (d, 1 H, both diastereomers),

3.93 (d, 1 H, diastereomer 1), 3.78 (d, 1 H, diastereomer 2), 3.69 - 3.60 (m, 3 H, both diastereomers), 2.40 - 2.32 (m, 1 H, both diastereomers), 1.69 - 1.63 (m, 1 H, both diastereomers), 1.54 - 1.40 (m, 1 H, both diastereomers), 0.98 (t, 3 H, diastereomer 1), 0.92 (t, 3 H, diastereomer 2).

Preparation 39: ((4S, 5S) -4-ethyl-5- (hydroxymethyl) -2-oxopyrrolidin-3-l) terbutyl carbamate (L70)

<img file="CU20160149A7_D0096.tif" />

Step 1. Synthesis of (7S, 7aS) -6-azido-7-efyl-3,3-d-methyltetrahydropyrrolo [1,2-c] oxazol5 (3H) -one (C93). LDA (2.0 M, 1.7 mL) was added to a solution of compound C54 (500 mg, 2.7 mmol) in THF (20 mL) at about -78 ° C. After about 30 minutes at about -78 ° C, a solution of 2.4.6-144 10% trisopropylbenzenesulfonyl azide (CAS 36982-84-0, 2.0 mL, 0.66 mmol) was added. After stirring at about -78 ° C for about 10 min, the solution was heated at about 25 ° C for about 1 h. Aqueous NH solution was added₄CI, and the mixture was extracted with EtOAc. The EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C93. Yield: 500 mg (82%).¹H NMR (400 MHz, CDCI₃) δ 4.43 (d, 1 Η), 4.13 - 4.08 (m, 1 H), 4.00- 3.97 (m, 1 H), 3.70 - 3.65 (m 1 H), 2.49 2.47 (m, 1 H), 1.65 ( s, 3 H), 1.75 - 1.42 (m, 2 H), 1.47 (s, 3 H), 0.90 (t, 3 H).

Step 2. Synthesis of (7R, 7aS) -6-amine-7-ethyl-3,3-dmethyltrahydropyrroloi1,2-cjoxazol5 (3H) -one (C94), to a compound solution C93 (500 mg, 2.2 mmol) in MeOH (30 mL), palladium on carbon (100 mg) was added, and the mixture was stirred under a hydrogen atmosphere (1 atm) for about 16 h. The mixture was filtered, and the filtrate was concentrated to obtain the title compound C94. Yield: 380 mg (86%). It was used in the next stage without further characterization.

Step 3. Synthesis of (4R, 5S) -3-amine-4-ethyl-5- (hydroxymethyl) pyrrolidine-2-one (C95). To a stirred solution of compound C94 (380 mg, 1.9 mmol) in 27 ml of acetonitrile and 3 ml of water, 4-toluenesulfonic acid (0.40 g, 2.3 mmol) was added. The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C and concentrated to obtain the title compound C95. Yield: 300 mg (47%).¹H NMR (400 MHz, dmso-d₆) δ 7.47 (d, 2 H),

7.11 (d, 2 H), 4.13-4.10 (m, 1 H), 3.71 - 3.56 (m, 2 H), 3.46-3.43 (m, 1 H), 2.07 (s, 3 H), 2.06 - 1.91 ( m, 1 Η), 1.50 - 1.47 (m, 1 H), 1.39 - 1.35 (m, 1 H), 0.92 (t, 3 H).

Step 4, Synthesis of ((4S, 5S) -4-ethyl-5- (hydroxymethyl) -2-oxoprolidin-3-yl) tert-butyl carbamate (L70). To a solution of compound C95 (300 mg, 1.9 mmol) and Et₃N (0.78 ml, 5.7 mmol) in THF (10 ml) and water (10 ml), di-t-butyl dicarbonate (0.83 ml, 3.8 mmol) was added. The mixture was kept at about 25 ° C for about 16 h. The reaction mixture was concentrated, and the residue was purified by chromatography to obtain the title compound L70. Yield: 280 mg (ca. 100%).¹H NMR (400 MHz, dmso-d₆) δ 7.76 (br. s, 1 H), 6.37 (d, 1 H), 5.44 (t, 1 H), 4.07 - 3.93 (m, 1 H),

3.48 - 3.43 (m, 2 H), 3.37 (br. M, 1 H), 2.36 - 2.33 (m, 1 H), 1.55 - 1.45 (m, 1 H), 1.37 (s, 9H), 1.33 - 1.28 (m, 1 H), 0.83 (t, 3 H).

Preparation 40: (1R, 4S, 5S, 6S) -4- (hydroxymethyl) -6-methyl-3-azabicyclo [3.1.0] hexane-2-one (L74)

-145 Stage 1. Synthesis of (3R, 5aR.6S, 6aS, 6bS) -3- (4-methoxyphenyl) -6-methyltetrahydro-1Hcyclopropa [3,41pyrrolof 1,2-c] oxazol-5 (3H) - one (C96). To a stirred suspension of ethyldiphenylsulfonium tetrafluoroborate (CAS 893-69-6, 31.36 g, 104 mmol) in THF (200 mL), LDA (2M, 65 mL, 130 mmol) was slowly added at about -78 ° C. The reaction mixture was maintained at about -78 ° C for about 1.5 h, at which time a solution of (3R, 7aS) -3- (4-methoxyphenyl) -1,7-dihydropyrrolo [1, 2-c] oxazol-5 (3H) -one (CAS 170885-07-1, 12.0 g, 51.9 mmol) in THF (90 mL). The reaction mixture was maintained at about -78 ° C for about

1.5 h and then heated to about 25 ° C. It was stirred for about 1.5 h at about 25 ° C before it was quenched with EtOAc and NaHCO solution₃. The EtOAc was separated, and the aqueous phase was reextracted with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C96. Yield 6.5 g (48%).¹H NMR (400 MHz, CDCI₃): δ 7.27 (d, 2 H), 6.84 (d, 2 H),

6.23 (s, 1 H), 4.14 (dd, 1 H), 3.88 (dd, 1 H), 3.78 (s, 3 H), 3.38 (dd, 1 H), 1.88 - 1.86 (m, 1 H), 1.79 - 1.77 (m, 1 H), 1.51 - 1.47 (m, 1 H), 1.14 (d, 3 H). It also occurred (3R_&gt;5aR, 6R, 6aS, 6bS) -3- (4-methoxyphenyl) -6-methyltetrahydro-1H-cyclopropa [3,4) pyrrolo [1,2c] oxazol-5 (3H) -one (C97). Yield: 1.5 g (11%).¹H NMR (400 MHz, CDCI₃): δ

7.29 (d, 2 H), 6.85 (d, 2 H), 6.26 (s, 1 H), 4.20 (t, 1 H), 3.78 (s, 3 H), 3.70 (t, 1 H), 3.53 ( dd, 1 H), 2.12 - 2.06 (m, 2 H), 1.61-1.55 (m, 1 H), 1.26 (d, 3 H).

Stage 2. Synthesis of (1R, 4S, 5S, 6S) -4- (hydroxymethyl) -6-methyl-3-azabicyclo3.1.01hexan-2one (L74). To a stirred solution of compound C96 (1.7 g, 6.6 mmol) in 45 ml of acetonitrile and 5 ml of water, 4-toluenesulfonic acid (64 mg, 0.33 mmol) was added. The reaction mixture was heated at about 90 ° C for about 45 min. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L74. Yield: 0.83 g (90%). ¹H NMR (400 MHz, CD₃OD) δ 3.40-3.59 (m, 3 H), 1.71 (dd, 1 H), 1.57 (dt, 1 H), 1.13 (d, 3 H), 1.02 (dd, 1 H).

Synthesis of (1R, 4S, 5S, 6R) -4- (hydroxymethyl) -6-methyl-3-azabicyclochloride 3.1.0jhexan-2-one (L75).

-146HO

This compound was prepared in the same manner as compound L74, substituting compound C97 for compound C96 in Step 2. ¹H NMR (400 MHz, CD₃CN) δ

6.12 (br. S „1 H), 3.45-3.54 (m, 2 H), 3.35 (br. S, 1 H), 3.26- 3.33 (m, 1 H), 1.69-1.80 (m, 2 H ), 1.23 - 1.39 (m, 1 H), 1.02 (d, 3 H).

Synthesis of (1R, 4S, 5S) -4- (hydroxymethyl) -3-azab¡cofcl.1.01hexan-2-one (L72).

HO

OR

H

HN

<img file="CU20160149A7_D0097.tif" />

H

This compound was prepared in the same manner as compound L74, substituting (3R, 5aR, 6aS, 6bS) -3- (4-methoxyphenyl) tetrahydride-1H-cyclopropa [3,4] pyrrolo [1,2-c ] oxazol5 (3H) -one (CAS 187742-05-8) by compound C96 in Step 2. ¹H NMR (400 MHz, CD₃OD) δ 3.47 - 3.61 (m, 3 H), 1.97 (ddd, 1 H), 1.75 - 1.86 (m, 1 H), 1.19 (td, 1 H), 0.59-0.68 (m, 1 H).

Synthesis of (lS, 4S, 5R) -4- (hydroxymethyl) -6,6-d¡met¡l-3-azabic¡clo | 3.1.01hexan-2-one

ÍLZ31

HO

OR

H

HN

<img file="CU20160149A7_D0098.tif" />

H

This compound was prepared in the same manner as compound L74, substituting (l-methyl) ethyldiphenylsulfonium tetrafluoroborate (CAS 40447-58-3) for CAS 893-69-6 in Step 1.

¹H NMR (400 MHz, CDCI₃) δ 7.04 (br. s., 1 H), 3.88 (br. s., 1 H), 3.61-3.70 (m, 1 H),

3.48-3.31 (m, 1 H), 3.44 (d, 1 H), 1.70 (d, 1 H), 1.51 (d, 1 H), 1.10 (s, 3 H), 1.10 (s, 3 H).

Synthesis of (1R, 4S, 5S, 6S) -6-ethyl-4- (hydroxymethyl) -3-azabicchloride 3.1.01hexan-2-one (L76).

OR

<img file="CU20160149A7_D0099.tif" />

-147 This compound was prepared in the same manner as compound L74, substituting propyldiphenylsulfonium tetrafluoroborate (CAS 14264-05-2) with CAS 893-69-6 in Step 1 to obtain (3R, 5aR, 6S, 6aS, 6bS) -6-etll-3- (4-methoxyphenyl) tetrahydro-1Hcyclopropa [3,4] plrolo- [1,2-c] oxazol-5 (3H) -one (C98), which was used in Step 2 . ¹H NMR (400 MHz, CDCI3) δ 6.56 (br. S., 1 H), 3.63 - 3.69 (m, 1 H), 3.62 (d, 1 H), 3.49 3.56 (m, 1 H), 3.48 (br s, 1 H), 1.63 (ddd, 1 H), 1.55 (ddd, 1 H), 1.29 - 1.39 (m, 2 H), 0.99 (t, 3 H), 0.95 - 1.05 (m, 1 H) . It also occurred in Stage 1 (3RI5aR, 6Rl6aS, 6bS) -6-ethyl-3- (4-methoxyphenyl) -tetrahydro-1H-cyclopropa [3,4] pyrrolo [1,2c] oxazol-5 (3H) - Ona (C99).¹H NMR (400 MHz, CDCI3) δ 7.30 (d, 2 H), 6.88 (d, 2 H),

6.28 (s, 1 H), 4.22 (dd, 1 H), 3.81 (s, 3 H), 3.73 (dd, 1 H), 3.53 (dd, 1 H), 2.14 (d, 2 H),

1.57 - 1.67 (m, 2 H), 1.51 (dd, 1 H), 1.08 (t, 3 H).

Synthesis of (1R, 4S, 5S, 6R) -6-ethyl-4- (hydroxymethyl) -3-azabiciclof3.1.01hexan-2-one (L77),

<img file="CU20160149A7_D0100.tif" />

This compound was prepared in the same manner as compound L74, substituting compound C99 for compound C96 in Step 2. ¹H NMR (400 MHz, CDCI₃) δ

6.99 (br. S, 1 H), 4.41 (br. S., 1 H), 3.68 (dd, 1 H), 3.57 (dd, 1 H), 3.40 - 3.48 (m, 1 H),

1.95 (ddt, 1 H), 1.71 -1.77 (m, 1 H), 1.34-1.43 (m, 2 H), 1.19-1 1.29 (m, 1 H), 1.02 (t, 3 H).

Preparation 41: (1S, 4S, 5R, 6S) -6- (fluoromethyl) -4- (hydroxymethyl) -3azabicyclo [3.1.Ojhexan-2-one (L79)

<img file="CU20160149A7_D0101.tif" />

Stage 1. Synthesis of 3- (4-methoxyphenyl) -5-oxohexahydro-1H-cyclopropa [3,4jpyrrolo [1,2cjoxazol-6-carboxylate of (3R, 5aS, 6S, 6aR, 6bS) -ethyl (C100 ). Bromide (carbetoxlmetl) dimethyl-lsulfon (CAS 5187-82-6, 15 g, 64.9 mmol) was dissolved in CHCI₃ (130 mi). A saturated aqueous solution of K₂CO₃ (61 ml) was added slowly with vigorous stirring and then aqueous NaOH solution (50%, 5.7 ml). Stirring continued for about 30 min. CHCI layer₃ it was separated, and the aqueous phase was extracted with CHCI₃ additional. CHCI combined extracts₃ they dried in K₂CO₃, I know

-148 filtered and concentrated to obtain a clear yellow liquid (9.58 g). This was dissolved in DMSO (100 ml). A solution of CAS 170885-07-1 (6.17 g, 26.7 mmol) in DMSO (33 ml) was added. The mixture was maintained for 3 days at about 25 ° C. Ethyl acetate (500 ml) was added, and the mixture was washed with brine (3 x 200 ml). The combined brine washes were extracted with EtOAc, and the combined EtOAc extracts were dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C100. Performance; 4.0 g (47%).¹H NMR (400 MHz, CDCI₃) δ

7.27 (d, 2 H), 6.86 (d, 2 H), 6.24 (s, 1 H), 4.19 - 4.24 (m, 1 H), 4.13 - 4.19 (m, 2 H),

3.96 (dd, 1 H), 3.79 (s, 3 H), 3.46 (dd, 1 H), 2.61 (dd, 1 H), 2.50 (ddd, 1 H), 2.24 (t, 1 H), 1.27 ( t, 3 H). 3- (4-Methoxylfenyl) -5-oxohexahydro-1Hcyclopropa [3,4] pyrrolo [1,2-c] oxazol-6-carboxylate (3R, 5aS, 6R, 6aR, 6bS) -et ¡(C101). Yield: 4.33 g (51%).¹H NMR (400 MHz, CDCI₃) δ 7.25 (d, 2 H), 6.84 (d, 2 H), 6.26 (s, 1 H), 4.20 (dd, 1 H), 4.08-4.15 (m, 1 H), 4.08 (q, 2 H ), 3.78 (s, 3 H), 3.46 (dd, 1 H), 2.37 - 2.45 (m, 3 H), 1.10 (t, 3 H).

Stage 2. Synthesis of (3R, 5aS, 6S, 6aS, 6bS) -6- (hydroxylmethyl) -3- (4-methoxyphenyljtetrahydro1H-cyclopropaf3,4jpyrrolo [1,2-c1oxazol-5 (3H) -one (C102), Lithium tritylborohydride (1 M, 22.1 mL) was slowly added to a solution of compound C100 (1.80 g, 5.7 mmol) in THF (5.3 mL) at -78 ° C. The mixture was maintained at about -78 ° C for about 1 h more before the slow addition of saturated aqueous NaHCO solution.₃ (4.0 mi). The mixture was heated to about 0 ° C, then aqueous hydrogen peroxide solution (30%, 3.0 mL) was added dropwise to control the resulting exothermic reaction. The mixture was then maintained for about 20 min at about 0 ° C. THF was evaporated under reduced pressure, and water (10 ml) was added. The mixture was extracted with DCM, and the combined DCM extracts were dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C102. Yield: 900 mg (58%).¹H NMR (400 MHz, CDCI₃) δ 7.28 (d, 1 H), 6.86 (d, 2 H), 6.24 (s, 1 H), 4.17 (dd, 1 H), 3.92 (dd, 1 H),

3.79 (s, 3 H), 3.61 (d, 2 H), 3.42 (dd, 1 H), 2.36 (br. S „1 H), 2.14 (dd, 1 H), 2.00 - 2.06 (m, 1 H ), 1.73 - 1.81 (m, 1 H). 400 mg (25%) of C108 aldehyde were also produced. Similarly, treatment of compound C101 with lithium tributylborohydride produced C104.¹H NMR (400 MHz, CDCI₃) δ 7.29 (d, 2 H), 6.87 (d, 2 H), 6.27 (s, 1

-149Η), 4.24 (dd, 1 Η), 3.97 (dd, 1 Η), 3.81 - 3.88 (m, 2 Η), 3.80 (s, 3 Η), 3.53 (dd, 1 Η),

2.21 - 2.32 (m, 2 Η), 1.81 -1.94 (m, 2 Η).

Stage 3. Synthesis of (3R, 5aS, 6S, 6aR, 6bS) -6- (fluoromethyl) -3- (4-methoxyphenyl) tetrahydro1 H -cyclopropar3,41pyrrolo [1,2-c1oxazol-5 (3H) - one (C103), A solution of compound C102 (200 mg 0.73 mmol) in DCM (3.6 ml) was treated with Et₃N (1.1 ml 7.3 mmol) and then with XtaIFluor-E (249 mg 1.1 mmol) and triethylamine trihydrofluoride (0.24 ml 1.4 mmol) in a polyethylene vial at about 25 ° C . The mixture was maintained for 3 days at about 25 ° C. Similarly, three additional experiments were prepared. NaHCO was added₃ aqueous (4 ml) to each vial with stirring. After about 20 min, the experiments were poured into NaHCO₃ aqueous and extracted with DCM. The combined DCM extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C103. Yield: 421 mg (52%).¹H NMR (400 MHz, CD₃CN) δ 7.27 (d, 2 H), 6.90 (d, 2 H), 6.06 (s, 1 H), 4.39 (ddd, 1 H), 4.20 - 4.34 (m, 1 H), 4.17 (dd, 1 H), 3.97 (dd, 1 H), 3.77 (s, 3 H), 3.38 (dd, 1 H), 2.25 - 2.32 (m, 1 H), 1.99 - 2.04 (m, 1 H), 1.90 (dt , 1 HOUR).

Stage 4. Synthesis of (1S, 4S, 5R, 6S) -6- (fluoromethyl) -4- (hydroxymethyl) -3azabicyclo [3.1.01hexan-2-one (L79). To a stirred solution of compound C103 (421 mg, 1.5 mmol) in 18 ml of acetonitrile and 2 ml of water, 4 toluenesulfonic acid (15 mg, 0.08 mmol) was added. The reaction mixture was heated at about 85 ° C for about 1.5 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L79. Yield: 209 mg (87%). ¹H NMR (400 MHz, CD₃OD) δ

4.43 (ddd, 1 H), 4.31 (ddd, 1 H), 3.51 - 3.66 (m, 3 H), 2.04 (ddd, 1 H), 1.93 (m, 1 H),

1.49 (qt, 1 H).

Synthesis of (1S, 4S, 5R, 6R) -6- (fluorometiD-4- (hydroxymethyl) -3-azabicyclo3.1.0jhexan-2one (L78).

HO

This compound was prepared in the same manner as compound L79, substituting compound C101 for compound C100 in Step 2. ¹H NMR (400 MHz, CDCI₃)

-150δ 4.40 (ddd, 1 Η), 4.28 (ddd, 1 Η), 3.69 (s, 2 Η), 3.53 - 3.61 (m, 1 Η), 1.89 (m, 2 Η),

1.45-1.55 (m, 1 Η).

Preparation 42: (1R, 4S.5S) -6- (2-fluoroethyl) -4- (h¡drox¡methyl) -3-azabic¡clof3.1.0jhexan-2ona (L80)

<img file="CU20160149A7_D0102.tif" />

Stage 1. Synthesis of (3-fluoropropyl) d -phenylsulfonium tetrafluoroborate (C105). A mixture of 1-iodo-3-fluoropropane (CAS 462-40-8, 8.80 g, 46.8 mmol), diphenyl sulfide (23.5 ml, 140 mmol) and silver tetrafluoroborate (1) (9) , 11 g, 46.8 mmol) in DCM (100 ml) was heated at about 38 ° C for about 19 h. The mixture was diluted with DCM (100 ml), filtered, and the filtrate was concentrated to about 50 ml in volume. After filtration, the filtrate was diluted with ethyl ether (100 ml). The white precipitate was separated from the liquid by decantation, and the precipitate was washed with two additional portions of DCM-ethyl ether, then dried under reduced pressure to obtain the title compound C105. Yield: 10.0 g (53%).¹H NMR (400 MHz, CDCI₃) δ 7.92 - 8.00 (m, 4 H), 7.64 - 7.78 (m, 6 H), 4.66 (dt, 2 H), 4.31 (t, 2 H),

2.21 (dtt, 2 H).

Stage 2. Synthesis of (3R, 5aR, 6aS, 6bS) -6- (2-fluoroethyl) -3- (4-methoxyphenyl) tetrahydro-1Hcyclopropaf3,41pyrrolof1,2-cloxazol-5 (3H) -one (C106 ), A solution of compound C105 (578 mg, 1.7 mmol) in THF (15 ml) was treated with tert-butyllithium solution (1.7 M,

1.32 mi) at around -78 ° C. The mixture was maintained for about 30 min at about -78 ° C, then a solution of CAS 170885-07-1 (200 mg, 0.87 mmol) in THF (5 mL) was added. After about 3 h at about -78 ° C, aqueous NH solution was added₄CI, and the mixture was extracted with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C106. Yield: 170 mg (67%).¹H NMR (400 MHz, CD₃CN) δ 7.27 (d, 2 H, diastereomer 1), 7.26 (d, 2 H, diastereomer 2), 6.90 (d, 2 H, diastereomer 1), 6.89 (d, 2 H, diastereomer 2), 6.07 (s, 1 H, diastereomer 1), 6.06 (s, 1 H, diastereomer 2), 4.60 (q, 2 H, diastereomer 1), 4.48 (q, 2 H, diastereomer 2), 4.24 (dd, 1 H, diastereomer 2), 4.20 (dd, 1 H, diastereomer 1), 4.13 (dd, 1 H, diastereomer 2),

-1513.92 (dd, 1 H, diastereomer 1), 3.78 (s, 3 H, diastereomer 1), 3.77 (s, 3 H, diastereomer 2), 3.48 (dd, 1 H, diastereomer 1), 3.34 (dd, 1 H, diastereomer 2).

Step 3._Synthesis of (1R, 4S, 5S) -6- (2-fluoroethyl) -4- (hydroxymethyl) -3azabiciclof3.1.0] hexane-2-one (L80). To a stirred solution of compound C106 (250 mg, 0.86 mmol) in 6 ml of acetonitrile and 1 ml of water, 4 toluenesulfonic acid (8 mg, 0.04 mmol) was added. The reaction mixture was heated at about 90 ° C for about 1 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L80. Yield: 140 mg (94%). ¹H NMR (400 MHz, CD₃CN) δ 4.39 - 4.64 (m, 2 H), 3.31 - 3.56 (m, 2 H), 3.07 - 3.30 (m, 1 H), 2.21 - 2.35 (m, 2 H), 0.96 - 1.89 (m, 3 H).

Preparation 43: (1 S, 4S, 5S, 6S) -4- (hydroxymethyl) -6- (methoxymethyl) -3azabic¡clof3.1 .OIhexan-2-one (L81)

<img file="CU20160149A7_D0103.tif" />

Stage 1. Synthesis of (3R, 5aS, 6S, 6aS, 6bS) -6- (methoxymethyl) -3- (4-methoxyphenyl) tetrahydro1 H -cyclopropa [3,4] pyrrolof1,2- C1xaxazol-5 (3H) -one (C107). To a stirred solution of compound C102 (400 mg, 1.46 mmol) in THF (10 mL), fresh silver (L) oxide (1.68 g, 7.27 mmol) was added and then iodomethane ( 0.46 ml, 7.27 mmol). The mixture was heated at about 60 ° C for about 16 h. The mixture was then cooled to about 25 ° C, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C107. Yield: 180 mg (43%).¹H NMR (400 MHz, CDCI₃) δ 7.26 (d, 2 H), 6.84 (d, 2 H), 4.15 (dd, 1 H), 3.92 (dd, 1 H),

3.78 (s, 3 H), 3.48 (dd, 1 H), 3.40 (dd, 1 H), 3.33 (s, 3 H), 3.21 (dd, 1 H), 2.13-2.11 (m, 1 H), 1.99-1.97 (m, 1 H), 1.78-1.75 (m, 1 H).

Stage 2. Synthesis of (1S, 4S, 5S, 6S) -4- (hydroxymethyl) -6- (methoxymethyl) -3-azabiciclof3.1.01hexan-2-one (L81). To a stirred solution of compound C107 (100 mg, 0.35 mmol) in 3.6 ml of acetonitrile and 0.4 ml of water, 4-toluensuifonic acid (3 mg,

0.02 mmol). The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L81.

Yield: 45 mg (76%). ¹H NMR (400 MHz, CDCI₃) δ 6.16 (br. s, 1 H), 3.68 (m, 2 -152Η), 3.56 (m, 1 Η), 3.48 (m, 1 Η), 3.33 (s, 3 Η), 3.17 (m, 1 Η), 1.82 (m, 2 Η), 1.37 (m, 1 Η).

Synthesis of (1S, 4S, 5S, 6R) -4- (hydroxymethyl) -6- (methoxymethyl) -3-azab3cycloi3.1. OIhexan-2one (L82).

<img file="CU20160149A7_D0104.tif" />

-OR

This compound was prepared in the same manner as compound L81, substituting compound C104 for compound 002 in Step 1. ¹H NMR (400 MHz, CDCI₃) δ 6.42 (br. s, 1 H), 3.73 - 3.68 (m, 1 H), 3.61 - 3.57 (m, 3 H), 3.42 - 3.38 (m, 1 H), 3.35 (s, 3 H ), 3.18 (br. M, 1 H), 2.08-2.04 (m, 1 H), 1.92-1.88 (m, 1 H), 1.68-1.62 (m, 1 H).

Synthesis of (1 S, 4S, 5S, 6S) -6 - ((benzyloxy) methyl) -4- (h¡drox¡met¡l) -3-azabic¡clof3.1. Olhexan2-one (L85).

<img file="CU20160149A7_D0105.tif" />

This compound was prepared in the same manner as compound L81, substituting (bromometll) benzene for iodomethane in Step 1. ¹H NMR (400 MHz, CDCI₃) δ 7.36 - 7.27 (m, 5 H), 5.67 (br. s, 1 H), 4.49 (dd, 2 H), 3.67 - 3.54 (m 4 H), 3.30 - 3.24 (m, 1 H), 1.85 - 1.76 (br. M, 2 H), 1.37-1.32 (br. M, 1 H).

Synthesis of (1 S, 4S, 5S, 6R) -6 - ((benzyloxy) methyl) -4- (hydroxymethyl) -3-azabcycle [3.1. Olhexan2-one (L86) .

OR

<img file="CU20160149A7_D0106.tif" />

This compound was prepared in the same manner as compound L81, substituting compound 004 for compound 002, and (bromomethyl) benzene with iodomethane, in Step 1. ¹H NMR (400 MHz, CDCI₃) δ 7.35 - 7.27 (m, 5 H), 5.96 (br. s, 1 H), 4.56 (d, 1 H), 4.48 (d, 1 H), 3.73 - 3.64 (m, 2 H), 3.60 - 3.55 (m, 2 H), 3.47 - 3.43 (m, 1 H),

2.06-2.00 (m, 1 H), 1.96-1.88 (m, 1 H), 1.72-1.64 (m, 1 H).

-153 Preparation 44: (1 S, 4S, 5R, 6S) -6- (difluoromethyl) -4- (hydroxymethyl) -3azabiciclof3.1.01hexan-2-one (L84)

<img file="CU20160149A7_D0107.tif" />

Stage 1, Synthesis of (3R, 5aS, 6S, 6aS, 6bS) -3- (4-methoxyphenyl) -5-oxohexahydro-1Hcyclopropa - ['3_l4-pyrrolo [1,2-c1oxazol-6-carbaldehyde (C108). A solution of compound C102 (9.20 g, 33 mmol) in DCM (167 ml) and water (1 ml) was treated with Dess Martin periodinan (28.3 g, 67 mmol) and stirred at about 25 ° C for about 2 h, at which time saturated aqueous NaHCO solution was added₃(200 ml), and stirring continued for about 30 min. The DCM was separated, and the aqueous phase was extracted with additional DCM. The combined DCM extracts were dried in MgSO₄₎ They were filtered and concentrated. The residue was purified by chromatography to obtain the title compound C108. Performance; 5.50 g (60%).¹H NMR (400 MHz, CD₃OD) δ 9.40 (d, 1 H), 7.32 (d, 2 H), 6.93 (d, 2 H), 6.17 (s, 1 H),

4.29 (dd, 1 H), 4.12 (dd, 1 H), 3.83 (s, 3 H), 3.53 (dd, 1 H), 2.89 (dd, 1 H), 2.64 (ddd, 1 H), 2.59 ( q, 1 H).

Step 2. Synthesis of (3R, 5aS, 6S, 6aR, 6bS) -6- (difluoromethyl) -3- (4-methoxyphenyl) tetrahydro1H-cyclopropaf3,4lpyrrolof1,2-c1oxazol-5 (3H) -one (C109). A solution of compound C108 (4.0 g, 14.6 mmol) in 1,2-dichloroethane (16.3 ml) and pyridine (24.1 ml) and a solution of DAST (7.7 ml, 58) were prepared mmol) in 1,2-dichloroethane (33 ml). A VaporTec flow reactor equipped with 10 ml loops was used for the experiment. A 10 ml portion of solution of compound C108 was added to the first loop. A 10 ml portion of DAST solution was added to the second loop. Both loops were injected together in heating coils at a rate of 0.2 ml / minute at about 90 ° C. After exiting the reactor coil, the eluate was passed through a plug of calcium carbonate. After the passage was completed, the eluate was diluted with 50 ml of DCM and washed with NaHCO₃ saturated aqueous. The DCM was separated, and the aqueous phase was extracted with additional DCM. The combined DCM extracts were dried in MgSO₄, filtered and concentrated. The experiment was repeated three more times, and the combined residues were purified by chromatography to obtain the title compound C109. Yield: 2.39 g (55%).¹H NMR (400 MHz, CDCI₃) δ 7.29 (d, 2 H), 6.87 (d, 2 H), 6.27 (s, 1 H), 5.87 -154 (td, 1 Η), 4.25 (dd, 1 Η), 3.98 (dd, 1 Η ), 3.81 (s, 3 Η), 3.47 (dd, 1 Η), 2.42 (dd, 1 Η),

2.30 (dd, 1 Η), 1.92 - 2.02 (m, 1 H). ¹⁹F NMR (376 MHz, CDCI3) δ -117.50, -120.09. Stage 3. Synthesis of (1S, 4S, 5R, 6S) -6- (dfluoromethyl) -4- (hydroxylmethyl) -3azabicyclo [3.1 .OIhexan-2-one (L84). To a stirred solution of compound C109 (2.39 g, 8.0 mmol) in 87 ml of acetonitrile and 14 ml of water, 4 toluenesulfonic acid (80 mg, 0.4 mmol) was added. The reaction mixture was heated at about 85 ° C for about 1 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L84. Yield: 1.41 g (99%).¹H NMR (400 MHz, CDCI3) δ 6.74 (br. S „1 H), 5.83 (td, 1 H), 3.67 - 3.76 (m, 2 H), 3.55 - 3.63 (m, 1 H), 2.03 - 2.14 (m, 2 H), 1.50 1.61 (m, 1 H). ¹⁹F NMR (376 MHz, CDCI₃) δ -116.67, -118.70.

Preparation 45: (1R, 4S, 5S, 6S) -6-fluoro-4- (hydroxymethyl) -3-azabicyclo [3.1.01hexan-2-one (L83)

<img file="CU20160149A7_D0108.tif" />

Stage 1. Synthesis of (3R, 5aR, 6S, 6aS, 6bS) -6-fluoro-3- (4-methoxyphenyl) tetrahydro-1Hc¡clopropaf3,41pyrrolof1,2-c] oxazol-5 (3H) -one (C110 ). A solution of CAS 17088507-1 (242 mg, 1.0 mmol) and A / - [(fIuoromethyl) oxodedophenyl-A⁴-sulfaniliden] -4-methylbenzenesulfonamide (CAS 1097193-08-2, 513 mg, 1.6 mmol) in THF (10 mL) was treated with lithium hexamethyldisilazide (1 M, 1.3 mL) at about -78 ° C. The mixture was stirred at about -78 ° C for about 10 min, then heated at about 25 ° C for about 3 h. Aqueous NH4CI solution was added, and the mixture was extracted twice with EtOAc. The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C110. Yield: 192 mg (70%).¹H NMR (400 MHz, CD3CN) δ 7.22 - 7.32 (m, 2 H), 6.85 - 6.95 (m, 2 H), 6.05 (s, 1 H), 4.88 (dd, 1 H), 4.17 (dd, 1 H), 3.94 (dd, 1 H), 3.77 (s, 3 H), 3.40 (dd, 1 H),

2.61 (ddd, 1 H), 2.38 (dd, 1 H).

¹⁹F NMR (376 MHz, CD₃CN) δ -201.68.

Stage 2. Synthesis of (1R, 4S, 5S, 6S) -6-fluoro-4- (hydroxymethyl) -3-azabinec [3.1.0jhexan2-one (L83). To a stirred solution of compound C110 (1.10 g, 4.2 mmol) in 54 ml

-155 acetonitrile and 6 ml of water, 4-toluenesulfonic acid (40 mg, 0.21 mmol) was added. The reaction mixture was stirred for about 6 h, then concentrated. The residue was purified by chromatography to obtain the title compound L83. Yield: 534 g (88%).¹H NMR (400 MHz, CDCI3) δ 5.72 (br. S „1 H), 4.41 - 4.63 (m, 1 H), 3.67 - 3.76 (m, 2 H), 3.55 - 3.65 (m, 1 H), 2.33 (dd, 1 H), 2.18 (dd, 1 H). ¹⁹F NMR (376 MHz, CDCI3) δ -205.65.

Preparation 46: (1R, 4S, 5S, 6R) -6-fluoro-4- (hydroxymethyl) -3-azab, cyclic 3.1.0jhexan-2-one

Í87)

<img file="CU20160149A7_D0109.tif" />

Stage 1. Synthesis of 4-methyl-A / - [(S) - (fluoromethyl) oxidophenyl-X⁴-sulfanilidenjbenzenesulfonamide (C111). A solution of CAS 170885-07-1 (330 mg, 1.4 mmol) and 4-methylA / - [(R) -methyloxidophenyl-X⁴-sulfaniliden] benzenesulfonamide (CAS 49620-56-6, 701 mg,

2.1 mmol) in THF (15 ml) was treated with lithium hexamethyldisilazide (1 M, 1.9 ml) at about -78 ° C. The mixture was stirred at about -78 ° C for about 10 min, then heated at about 25 ° C for about 3 h. Aqueous NH solution was added₄CI, and the mixture was extracted twice with EtOAc. The combined EtOAc extracts were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C111. Yield: 60 mg (16%). It was used in the next stage without further characterization.

Stage 2. Synthesis of (1R, 4S, 5S, 6R) -6-fluoro-4- (hydroxymethyl) -3-azabicyclo [3.1.0lhexan2-one (L87). To a stirred solution of compound C111 (60 mg, 0.23 mmol) in 9 ml of acetonitrile and 1 ml of water, 4-toluenesulfonic acid (6 mg, 0.03 mmol) was added. The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L87. Yield: 25 mg (75%). It was used in the next stage without further characterization. Preparation 47 (1R, 4S, 5S, 6S) -6-fluoro-4- (hydroxymethyl) -6-methyl-3-azabicyclo [3.1.01hexan-2-one (L88)

-156-

<img file="CU20160149A7_D0110.tif" />

Stage 1. Synthesis of (3R, 5aR, 6S, 6aS, 6bS) -6-fluoro-3- (4-methoxyphenyl) -6-methyltetrahydro1 H -cyclopropaí3,4lpirrolof 1,2-c1oxazol-5 (3H) -one ( Cl 12). A solution of CAS 170885-07-1 (430 mg, 1.9 mmol) and 4-methyl- / V - [(R) - [(1 S) -1-fluoroethyl] -oxidophenyl-X⁴sulfaniliden] benzene sulfonamide (CAS 1422176-84-8, 952 mg, 2.8 mmol) in THF (19 ml) was treated with lithium hexamethyldisllazide (1 M, 2.4 ml) at -78 ° C. The mixture was stirred at about -78 ° C for about 10 min, then heated at about 25 ° C for about 3 h. Aqueous NH4CI solution was added, and the mixture was extracted twice with EtOAc. The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C112. Yield: 200 mg (39%).¹H NMR (400 MHz, CDCI3) δ 7.26 (d, 2 H), 6.88 (d, 2 H), 6.24 (s, 1 H), 4.25 (dd, 1 H), 3.81 (s, 3 H), 3.76 - 3.84 (m, 1 H), 3.50 - 3.57 (m, 1 H), 2.39 - 2.54 (m, 2 Η),

1.56 (s, 3 H). ¹⁹F NMR (376 MHz, CDCI₃) δ -157.20. There was also (3R, 5aR, 6R, 6aS, 6bS) -6-fluoro-3- (4-methoxyphenyl) -6-methyltetra-hydro-1 Hcyclopropa [3,4] pyrrolo [1,2-c] oxazol- 5 (3H) -one (C113). It was used in the next stage without further characterization.

Step 2. Synthesis of (1R, 4S, 5S, 6S) -6-fluoro-4- (hydroxymethyl) -6-methyl-3azabicyclo [3.1. OIhexan-2-one (L88), To a stirred solution of compound C112 (211 mg, 0.76 mmol) in 9 ml of acetonitrile and 1 ml of water, 4 toluenesulfonic acid (7 mg, 0.04 mmol) was added. The reaction mixture was heated at about 90 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L88. Yield: 110 mg (91%). ¹H NMR (400 MHz, CDCI3) δ 6.20 (br. S., 1 H), 3.69 - 3.78 (m, 1 H), 3.54 - 3.68 (m, 2 H), 2.68 (s, 1 H), 2.32 ( dd, 1 H), 2.11 (dd, 1 H), 1.67 (s, 3 H). ¹⁹F NMR (376 MHz, CDCI3) δ -161.43.

Synthesis of (1R, 4S, 5S, 6R) -6-fluoro-4- (hydroxymethyl) -6-methyl-3-azabicyclo [3.1.0] hexane-2one (L89).

157-

<img file="CU20160149A7_D0111.tif" />

This compound was prepared in the same manner as compound L88, substituting compound C113 for compound C112 in Step 2. It was used in the next step without further characterization.

Preparation 48: (1 R, 4S, 5S) -4- (hydroxymethyl) -1-methyl-3-azabicichlor3.1. Ojhexan-2-one

Í91)

<img file="CU20160149A7_D0112.tif" />

Stage 1. Synthesis of (3R, 5aR, 6aS, 6bS) -3- (4-methoxyphenyl) -5a-methyltetrahydro-1Hcyclopropaf3,41-pyrrolof1,2-c1oxazol-5 (3H) -one (C114), Very added Slowly IDA (2M, 0.31 ml) to a solution of (3R, 5aR, 6aS, 6bS) -3- (4-methoxyphenyl) tetrahydro-1Hcyclopropa [3,4] bolus [1,2- c] oxazol-5 (3H) -one (CAS 187742-05-8, 150 mg, 0.61 mmol) and iodomethane (0.20 mL, 3 mmol) in THF (3 mL) at about -78 ° C . After about 1 h, 0.31 ml of LDA and 0.2 ml of additional iodomethane were added. The mixture was heated at about -20 ° C for about 45 min and heated at about 25 ° C for about 1.5 h. The mixture was poured into NaHCO solution.₃ and extracted twice with EtOAc. The combined EtOAc extracts were dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C114. Yield: 31 mg (20%).¹H NMR (400 MHz, CD₃CN) δ 7.27 (d, 2 H), 6.89 (d, 2 H), 6.07 (s, 1 H), 4.13 (dd, 1 H), 3.81 (dd, 1 H), 3.77 (s, 3 H) , 3.31 (dd, 1 H), 2.06 (dd, 1 H), 1.30 (s, 3 H), 1.08 - 1.18 (m, 2 H).

Step 2. Synthesis of (1R, 4S, 5S) -4- (hydroxymethyl) -1-methyl-3-azabiciclof3.1.01hexan-2-one (L91), To a stirred solution of compound C114 (41 mg, 0, 16 mmoi) in 2 ml of acetonitrile and 0.2 ml of water, 4-toluenesulfonic acid (2 mg, 0.008 mmol) was added. The reaction mixture was heated at about 90 ° C for about 45 min. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L91.

-158 Yield: 21 mg (93%). ¹H NMR (400 MHz, CD₃OD) δ 3.46-3.55 (m, 2 H), 3.43 (q, 1 H), 1.75 (dd, 1 H), 1.28 (s, 3 H), 0.98 (dd, 1 H), 0.68 (t, 1 H).

Preparation 49 (1 S, 4S, 5R, 6S) -1 -fluoro-4- (h¡drox¡met¡l) -6-methyl-3-azab¡c¡ofof 3.1, Q '| hexan-2- Ona (L92)

<img file="CU20160149A7_D0113.tif" />

Stage 1. Synthesis of (3R, 7aS) -6-fluoro-3- (4-methoxyphenyl) tetrah ¡drop¡rrolof1,2-c1oxazol5 (3H) -one (C115). To a solution of (3R, 7aS) -3- (4-methoxyphenyl) tetrahydropyrrolo [1,2cjoxazol-5 (3H) -one (CAS 170885-05-9, 16.0 g, 68.59 mmol) in THF ( 160 ml), LDA (2 M, 48 ml) was added at about -78 ° C and stirred for about 30 min. A solution of NFSI (22.68 g, 72 mmol) in THF (80 ml) was added at about -78 ° C. After about 30 min at about -78 ° C, the mixture was heated at about 25 ° C for about 30 min. EtOAc and water were added, and the phases separated. The aqueous phase was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C115. Yield: 12.4 g (72%).¹H NMR (400 MHz, CDCI₃) δ

7.36 (d, 2 H), 6.88 (d, 2 H), 6.22 (s, 1 H), 5.14 (dd, 1 H), 4.40-4.29 (m, 2 H), 3.79 (s, 1 H), 3.46 (dd, 1 H), 2.62 - 2.51 (m 1 H), 2.23 - 2.07 (m 1 H).

Stage 2. Synthesis of (3R, 7aS) -6-fluoro-3- (4-methoxyphenyl) -6- (phenyllanlanyl) tetrahydropyrrolo [1,2-c1oxazol-5 (3H) -one (C116 ). To a stirred solution of compound C115 (12.4 g, 49 mmol) in THF (130 mL), LDA (2 M, 35 mL) was added at about -78 ° C and stirred for about 30 min before that a solution of diphenyl diselenide (16.96 g, 54 mmol) in THF (70 ml) was added. The mixture was kept at about -78 ° C for about 30 min, then heated at about 25 ° C for about 30 min. EtOAc and water were added, and the phases separated. The aqueous phase was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C116. Yield: 13 g (65%). It was used in the next stage without further characterization.

-159 Stage 3. Synthesis of (3R, 7aS) -6-fluoro-3- (4-methoxyphene) -1,7a-dih, drop it [1,2-cxaxazol-5 (3H) -one (C117). A solution of compound C116 (13.0 g, 32 mmol) in DCM (260 mL) and pyridine (5.7 mL, 70 mmol) was treated with hydrogen peroxide (30%,

11.9 mi, 106 mmol) at about 0 ° C. The mixture was kept at about 0 ° C for about 30 min and heated at about 25 ° C for about 2 h before it was diluted with DCM and water. The DCM was separated, and the aqueous phase was extracted with DCM. The combined DCM extracts were washed with water, brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C117. Yield: 4.6 g (58%).¹H NMR (400 MHz, CD₃CN) δ 7.43 (d, 2 H), 6.96 (d, 2 H), 6.72 (dd, 1 H), 5.91 (s, 1 H),

4.59 (m, 1 H), 4.36 (dd, 1 H), 3.80 (s, 3 H), 3.29 - 3.36 (m, 1 H). ¹⁹F NMR (376 MHz, CD₃CN) δ -137.11.

Stage 4. Synthesis of (3R, 5aS, 6S, 6aR, 6bS) -5a-fluoro-3- (4-methoxyphenyl) -6-methyltetrahydro1H-c¡clopropaf3,4lp¡rrolof1,2-c1oxazol-5 (3H) - one (C118). To a stirred suspension of ethyldiphenylsulfonium tetrafluoroborate (CAS 893-69-6, 5.31 g, 17 mmol) in DME (62 mL), LDA (2M, 8.0 mL, 16 mmol) was slowly added to about -55 ° C The reaction mixture was maintained at about -55 ° C for about 45 min, at which time it was heated to about -35 ° C, and a solution of compound C117 (1.99 g, 8.0 mmol) was added. ) in DME (20 mi). The reaction mixture was maintained at about -30 ° C for about 1.5 h, then NaHCO was added.₃ aqueous and EtOAc. The EtOAc was separated, and the aqueous phase was extracted with EtOAc. The combined EtOAc extracts were dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C118. Yield: 362 mg (16%).¹H NMR (400 MHz, CD₃CN) δ

7.28 (d, 2 H), 6.90 (d, 2 H), 6.12 (s, 1 H), 4.17 (dd, 1 H), 3.78 (s, 3 H), 3.66 - 3.75 (m, 1 H), 3.45 (dd, 1 H), 2.33 (dd, 1 H), 1.64 (d, 1 H), 1.25 (dd, 3 H). There was also (3R, 5aS, 6R, 6aR, 6bS) -5a-fluoro-3- (4-methoxyphenyl) -6-methyltrahydro-1Hcyclopropa [3,4] pyrrolo [1,2-c] oxazole -5 (3H) -one (C119). Performance; 816 mg (37%).¹H NMR (400 MHz, CD₃CN) δ 7.30 (d, 2 H), 6.92 (d, 2 H), 6.15 (s, 1 H), 4.20 - 4.24 (m, 1 H), 3.78 (s, 3 H), 3.57 - 3.62 (m , 2 H), 2.72 (dd, 1 H), 2.13 - 2.23 (m, 1 H), 1.15 (dd, 3 H).

Step 5. Synthesis of (1S, 4S, 5R, 6S) -1-fluoro-4- (hydroxymethyl) -6-methyl-3-azabiciclof3.1.0jhexan-2-one (L92) To a stirred solution of compound C118 (400 mg, 1.4 mmol) in

-16018 ml of acetonitrile and 2 ml of water, 4-toluenesulfonic acid (14 mg, 0.07 mmol) was added. The reaction mixture was maintained at about 25 ° C for about 12 h, then concentrated, and the residue was purified by chromatography to obtain the title compound L92. Yield: 181 mg (79%).¹H NMR (400 MHz, CDCI₃) δ 6.07 (br, s., 1 H), 3.66 - 3.81 (m, 1 H), 3.54 - 3.67 (m, 1 H), 3.36 - 3.50 (m, 1 H), 1.77 -1.87 (m, 2H ), 1.29 (d, 3 H).

Synthesis of (1S, 4S, 5R, 6R) -1-fluoro-4- (h¡drox¡metil) -6-met¡l-3-azab¡c¡ofof3.1.0jhexan-2ona (L93).

<img file="CU20160149A7_D0114.tif" />

This compound was prepared in the same manner as compound L92. substituting compound C119 for compound C118 in Step 5.¹H NMR (400 MHz, CD₃OD) δ 3.63 (dd, 2 H), 3.28 (dt, 1 H), 2.38 (dd, 1 H), 1.95 - 2.07 (m, 1 H), 1.07 (dd, 3 H).

Preparation 50: (1R, 4S, 5S) -4- (hydroxymethyl) -5-methyl-3-azabic-clof 3.1.11 hexan-2-one

IL941

<img file="CU20160149A7_D0115.tif" />

Stage 1. Synthesis of (3R, 7S, 7aS) -3- (4-methoxyphenyl) -7-methyltetrahydropyrrolof1,2-cloxazol5 (3H) -one (C120). A suspension of cuprous bromide-dimethyl sulfide complex (2.24 g, 10.8 mmol) in ether (30 ml) was cooled to about -10 ° C, and a solution of methyl lithium (1, 6 M, 13.5 mi). The mixture was then cooled to about -78 ° C, and TMSCI (1.36 mL, 10.8 mmol) was added slowly. After the addition was completed, the mixture was maintained for about 15 min before slowly adding (3R, 7aS) -3- (4-methoxyphenyl) -1,7adihydropyrrolo [1,2-c] oxazol-5 (3H) -one (CAS 170885-07-1, 1.00 g, 4.3 mmol) in THF (20 mL). The mixture was kept for an additional 2 h at about -78 ° C before it was heated to about 25 ° C. The mixture was kept at about 25 ° C for about 1 h before it was treated with a mixture of NH₄Saturated aqueous CI and ammonium hydroxide. The ether layer was separated, and the aqueous phase was extracted.

-161 twice with EtOAe. The combined extracts were dried in MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C120. Yield: 457 mg (43%).¹H NMR (400 MHz, CDCI₃) δ

7.36 (d, 2 H), 6.89 (d, 2 H), 6.31 (s, 1 H), 4.20 (dd, 1 H), 3.81 (s, 3 H), 3.77 (q, 1 H),

3.59 (dd, 1 H), 2.61 - 2.72 (m, 1 H), 2.44 - 2.55 (m, 1 H), 2.29 - 2.42 (m, 1 H), 1.23 (d, 3 H).

Step 2. Synthesis of (3R, 7R, 7aS) -3- (4-methoxyphenyl) -7-methyl-6- (phenylselanyl) tetrahydropyrrolo [1,2-c1oxazol-5 (3H) -one (C121), A stirred solution of compound C120 (450 mg, 1.8 mmol) in THF (10 mL), LDA (2 M, 1.18 mL) was added at about -78 ° C and stirred for about 30 min before that a solution of phenyl sebeniium chloride (462 mg, 2.4 mmol) in THF (5 ml) be added. The mixture was kept at about -78 ° C for about 30 min, then heated at about 25 ° C for about 2 h. EtOAe and water were added, and the phases separated. The aqueous phase was extracted with EtOAe. The combined EtOAe extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C121. Yield: 343 mg (47%). It was used in the next stage without further characterization.

Step 3. Synthesis of (3R, 7aS) -3- (4-methoxyphenyl) -7-methyl-1,7a-dihydropyrrolof1,2-c1oxazol5 (3H) -one (C122). A solution of compound C121 (343 mg, 0.85 mmol) in DCM (15 mL) and pyridine (0.15 mL) at about 0 ° C was treated with 30% hydrogen peroxide solution (0.17 mL) , 2.8 mmol). The mixture was kept at about 0 ° C for about 30 min before it was slowly heated to about 25 ° C. After about 3 h, the mixture was diluted with DCM (10 ml) and washed with saturated aqueous NaHCO solution.₃. The combined DCM extracts were washed with brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C122. Yield: 143 mg (68%).¹H NMR (400 MHz, CDCI₃) δ 7.44 (d, 2 H), 6.91 (d, 2 H),

6.18 (s, 1 H), 5.82 (s, 1 H), 4.39 - 4.49 (m, 1 H), 4.21 (s, 1 H), 3.82 (s, 3 H), 3.47 (s, 1 H), 2.09 (d, 3 H).

Step 4. Synthesis of (3R, 5aR, 6aS, 6bS) -3- (4-methoxyphenyl) -6a-methyltetrahydro-1Hc¡clopropa [3,4jpyrrolof1,2-c1oxazol-5 (3H) -one (C123). Sodium hexamethyldisilazide (1 M, 0.57 ml) was added to a suspension of trimethylsuifoxonium iodide (128 mg, 0.57 mmol) in DMSO (2 ml) at about 25 ° C. The mixture was kept at around 25

-162 ° C for about 30 min, then heated to about 55 ° C for about 30 min. The mixture was cooled to about 25 ° C, then a solution of compound C122 (100 mg, 0.41 mmol) in THF (1 ml) was added. After about 18 h, NH was added₄Aqueous CI, and the mixture was extensively extracted with ethyl ether. The combined ether extracts were washed with water and brine, dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C123. Yield: 55 mg (52%).¹H NMR (400 MHz, CD₃CN) δ 7.24 - 7.29 (m, 2 H) 6.86 - 6.92 (m, 2 H) 6.06 (s, 1 H)

4.11 - 4.16 (m, 1 H) 3.92 (ddd, 1 H) 3.77 (s, 3 H) 3.50 (dd, 1 H) 1.72 - 1.77 (m, 1 H)

1.30 (s, 3 H) 1.19 (s, 1 H) 1.17 (d, 1 H).

Step 5. Synthesis of (1R, 4S, 5S) -4- (hydroxymethyl) -5-methyl-3-azabic-cyclic 3.1.01hexan-2-one (L94). To a stirred solution of compound C123 (200 mg, 0.77 mmol) in 18 ml of acetonitrile and 2 ml of water, 4-toluenesulfonic acid (7 mg, 0.04 mmol) was added. The reaction mixture was heated at about 95 ° C for about 1 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L94. Yield: 95 mg (87%). ¹H NMR (400 MHz, CDCI₃) δ 6.04 (br. s., 1 H) 3.81 (dd, 1 H) 3.62 - 3.68 (m, 1 H) 3.57 - 3.61 (m, 1 H) 2.12 (br. s „1 H) 1.62 - 1.68 ( m, 1 H) 1.30 (s, 3 H) 0.99 (dd, 1 H) 0.85 - 0.89 (m, 1 H).

Synthesis of (1R, 4S, 5S) -5-et¡l-4- (h¡droximet¡l) -3-azabicyclof3.1.0jhexan-2-one (L95)

OR

HO

This compound was prepared in the same manner as compound L94, substituting ethylmagnesium chloride for methyl lithium in Step 1. It was used in the next stage without further characterization.

Preparation 51; (1S, 4S, 5R) -1-fluoro-4- (hydroxymethyl) -3-azab¡cyclof3.1.Qjhexan-2-one (L96)

HO

-163 Stage 1. Synthesis of (3R, 7R, 7aS) -3-phen-l-7-vln tetrahydropyrrolof1,2-c1oxazol-5 (3H) -one (C124). A suspension of cuprous bromide-dlmeyl sulfide complex (10.4 g, 50 mmol) in ether (70 ml) was cooled to about -10 ° C, and a solution of vinyl magnesium bromide (1 M, slowly added) 100 mi) The mixture was stirred at about -10 ° C for about 30 min. The mixture was then cooled to about -78 ° C, and TMSCI (9.2 mL, 73 mmol) was added slowly. After the addition was completed, the mixture was maintained for about 15 min before slowly adding (3R, 7aS) -3-phenyl-1,7a-dihydropyrrolo [1,2-c] oxazol-5 (3H ) -one (CAS 13410765-6, 6.70 g, 33 mmol) in THF (70 ml). The mixture was maintained for an additional 4 h at about -78 ° C before it was treated with a mixture of NH₄Saturated aqueous CI and ammonium hydroxide. The ether layer was separated, and the aqueous phase was extracted twice with EtOAc. The combined extracts were dried over MgSO.₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C124. Yield: 5.53 g (72%).¹H NMR (400 MHz, CDCI3) δ 7.42 - 7.47 (m, 2 H), 7.31 - 7.40 (m, 3 H), 6.39 (s, 1 H), 5.88 (ddd, 1 H), 5.12 - 5.20 (m , 2 H), 4.19 (dd, 1 H), 3.96 (q, 1 H), 3.71 (dd, 1 H), 2.95 (dq, 1 H), 2.63 - 2.81 (m, 2 H). Stage 2, Synthesis of (3R, 7R, 7aS) -6-fluoro-3-phenyl-7-vinyltetrah¡dropirrolof1,2-cjoxazol5 (3H) -one (C125), A solution of LDA was generated from n-butyllithium (2.5 M, 1.1 ml) and diisopropylamine (0.73 ml, 5.2 mmol) in THF at about 0 ° C for about 1 h. A solution of compound C124 (1.00 g, 4.4 mmol) in THF (40 mL) was treated with LDA solution at about -78 ° C. After about 30 min, a solution of NFSI (1.70 g, 5.2 mmol) in THF (5 mL) was added. The mixture was heated at about 25 ° C for about 16 h. Saturated aqueous NH4CI solution was added, and the mixture was extracted with EtOAc (50 mL). The EtOAc extract was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C125. Yield: 441 mg (41%).¹H NMR (400 MHz, CDCI3) δ 7.33-7.50 (m, 5 H), 6.48 (s, 1 H), 5.95 (ddd, 1 H), 5.31 5.38 (m, 2 H), 5.22 (dd, 1 H ), 4.22-433 (m, 1 H), 3.75-3.86 (m, 2 H), 2.93-3.08 (m, 1 H). ¹⁹F NMR (376 MHz, CDCI₃) δ -194.19, -198.01.

Step 3. Synthesis of (3R, 7S, 7aS) -6-fluoro-7- (hydroxymethyl) -3-phenyltetrah, dropyrrolof1,2c1oxazol-5 (3H) -one (C126). A flow of ozonized oxygen was bubbled through a solution of compound C125 (440 mg, 1.8 mmol) in DCM (6 mL) and MeOH (2 mL) at about -78 ° C. After a blue color persisted in the mixture, the

-164 mixture was treated with dimethyl sulfide (3 ml). NaBH was added₄ (202 mg, 5.3 mmol), and the mixture was stirred at about -78 ° C for about 30 min before it was heated at about 0 ° C for about 30 min. The mixture was treated with saturated aqueous NH solution.₄CI and extracted with EtOAc. The EtOAc extract was washed with brine, dried over MgSO₄, was filtered and concentrated. The residue was purified by chromatography to obtain the title compound C126. Yield: 207 mg (46%).¹H NMR (400 MHz, CDCI3) δ 7.31 - 7.50 (m, 5 H), 6.44 (s, 1 Η), 5.31 (dd, 1 H), 4.36 (dd, 1 H), 4.04 (dt, 1 H) , 3.87 - 3.97 (m, 2 H), 3.76 (dd, 1 H), 2.49 - 2.69 (m, 1 H), 1.69 (t, 1 H). ¹⁹F NMR (376 MHz, CDCI3) δ -193.64.

Step 4, Synthesis of (3R, 7R, 7aS) -7- (bromomethyl) -6-fluoro-3-phenyltetrahydropyrrolo [1,2C1oxazol-5 (3H) -one (C127). A solution of compound C126 (202 mg, 0.8 ml) in DCM was treated with pyridine (0.13 ml, 1.6 mmol) and carbon tetrabromide (323 mg, 1.0 mmol). Triphenylphosphine (258 mg, 1.0 mmol) was added slowly to the mixture. The mixture was kept around 2 h at about 25 ° C, then NaHCO was added₃saturated aqueous, and the mixture was extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over MgSO_4&gt; They were filtered and concentrated. The residue was purified by chromatography to obtain the title compound C127. Yield: 185 mg (73%).¹H NMR (400 MHz, CDCI₃) δ

7.34 - 7.47 (m, 5 H), 6.45 (s, 1 H), 5.21 (dd, 1 H), 4.41 - 4.49 (m, 1 H), 3.82 - 3.89 (m, 2 H), 3.76 - 3.81 ( m, 1 H), 3.56 (dd, 1 H), 2.74-288 (m, 1 H). ¹⁹F NMR (376 MHz, CDCIs) δ -193.19.

Stage 5. Synthesis of (3R, 5aS, 6aR, 6bS) -5a-fluoro-3-phenol-tetrahydro-1Hcclopropa [3,4jprrolo-f1,2-c1oxazol-5 (3H) -one (C128) . A solution of compound C127 (185 mg, 0.59 mmol) in THF (10 ml) was treated with lithium hexamethyldisilazide (1 M, 0.62 ml) at about -78 ° C. After about 15 min at about -78 ° C, the mixture was heated at about 0 ° C for about 30 min, then an additional portion of lithium hexamethyldisilazide (1 M, 0.31 ml) was added. After about 30 min more at about 0 ° C, the mixture was treated with saturated aqueous NH solution₄CI and extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C128. Yield: 110 mg (80%).¹H NMR (400 MHz, CDCI₃) δ

7.29 - 7.44 (m, 5 H), 6.40 (s, 1 H), 4.26 (dd, 1 H), 3.61 - 3.69 (m, 1 H), 3.53 - 3.60 (m, 1

-165Η), 2.60 (td, 1 Η), 1.90 (ddd, 1 Η), 1.44 (dt, 1 Η). ¹⁹F NMR (376 MHz, CDCI₃) δ 208.58.

Stage 6. Synthesis of (1S, 4S, 5R) -1-fluoro-4- (h¡drox¡metil) -3-azab¡ciclof3.1.Qjhexan-2ona (L96). To a stirred solution of compound C128 (110 mg, 0.47 mmol) in 18 ml of acetonitrile and 2 ml of water, 4-toluenesulfonic acid (5 mg, 0.02 mmol) was added. The reaction mixture was maintained at about 25 ° C for about 6 h, then heated at about 60 ° C for about 6 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L96. Yield 53 mg (77%). It was used in the next stage without further characterization.

Preparation 52: (1R, 4S, 5S) -4- (hydroxymethyl) -3-azabiciclof3.2.01heptan-2-one (L97)

<img file="CU20160149A7_D0116.tif" />

Step 1. Synthesis of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -4-oxo-3-azabicyclo [3.2.0] heptan-3-carboxylate of (1S, 2S, 5R) -ter-butyl (C129), A solution of (S) -ter-butyl 2- (((terbutyldimethylsili [) oxy) methyl) -5-oxo-2,5-dihydro-1 H-pyrrol-1-carboxylate (CAS 81658-27-7, 1.00 g, 3.1 mmol) in acetone (330 ml) was saturated with ethylene gas and irradiated with ultraviolet light at about -20 ° C for about 6 h. A continuous flow of ethylene gas was maintained during irradiation. The mixture was then concentrated, and the residue was purified by chromatography to obtain the title compound C129. Yield: 250 mg (23%).¹H NMR (400 MHz, CDCI₃) δ 3.89 (s, 1 H), 3.81 (dd, 1 H), 3.59 (d, 1 H), 3.03 (t, 1 H), 2.88 (q, 1 H), 2.49 - 2.44 (m, 1 H ), 2.29 2.25 (m, 1 H), 2.11 - 1.99 (m, 2 H), 1.54 (s, 9 H), 0.84 (s, 9 H), 0.06 (m, 6 H).

Stage 2. Synthesis of 2- (h¡drox¡met¡l) -4-oxo-3-azab¡c¡clof3.2.0] heptan-3-carboxylate (1S, 2S, 5R) -ter-but (C130), A solution of compound C129 (568 mg, 1.6 mmol) in THF (8 ml) was treated with a solution of tetrabutylammonium fluoride (1 M, 3.2 ml) at about 25 ° C . After about 4 h, the mixture was poured into water and extracted with EtOAc. The combined EtOAc extracts were dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C130. Yield: 357 mg (93%).¹H NMR (400 MHz, CDCI₃) δ 6.66 (br. s., 1 H), 3.90 - 4.01 (m, 1 H), 3.79 - 3.86 (m, 1 H), 3.61 (t, 1 H), 2.91 - 2.99

-166 (m, 1 Η), 2.78 - 2.88 (m, 1 Η), 2.41 - 2.52 (m, 1 Η), 2.30 - 2.41 (m, 1 Η), 2.01 - 2.16 (m, 2 Η), 1.46 (s, 9 Η).

Stage 3. Synthesis of (1R, 4S, 5S) -4- (hydroxymethyl) -3-azabicyclo3.2.0jheptan-2-one (L97).

Compound C130 (357 mg, 1.5 mmol) was dissolved in DCM (1 ml) at about 25 ° C. A mixture of DCM (1 ml) and TFA (1 ml) was added, and the mixture was maintained at about 25 ° C for about 2 h. It was then concentrated to dryness to obtain the title compound L97. Yield: 211 mg (100%).¹H NMR (400 MHz, CDCI₃) δ 5.55 (br. s., 2 H), 4.34 (dd, 1 H), 4.17 (dd, 1 H), 3.82 (t, 1 H), 3.02 - 3.18 (m, 1 H), 2.82 - 2.99 (m, 1 H), 2.48 - 2.64 (m, 1 H), 2.36 - 2.48 (m, 1 H), 2.02 - 2.26 (m, 2 H).

Preparation 53: (1S, 4S, 5R) -1-fluoro-4- (hydroxymethyl) -3-azabiciclof3.2.0] heptan-2-one

Í98)

OR

HO

Stage 1. Synthesis of (3R, 5aS, 7aR, 7bS) -5a-fluoro-3- (4-methoxyphenyl) hexahydrocclobutaf3,4jpyroloi1,2-cjoxazol-5 (3H) -one (C131). A solution of compound C117 (300 mg, 1.2 mmol) in acetone (450 ml) was saturated with ethylene gas and irradiated with ultraviolet light at about -20 ° C for about 6 h. A continuous flow of ethylene gas was maintained during irradiation. The mixture was then concentrated, and the residue was purified by chromatography to obtain the title compound C131. Yield: 170 mg (51%). ¹H NMR (400 MHz, CDCI₃) δ 7.38 (d, 2 H), 6.90 (d, 2 H),

6.37 (s, 1 H), 4.21 (dd, 1 H), 3.81 (s, 3 H), 3.78 - 3.74 (m, 1 H), 3.32 (dd, 1 H), 3.06 3.01 (m, 1 H) , 2.65 - 2.56 (m, 2 H), 2.49 - 2.42 (m, 1 H), 1.67 - 1.62 (m, 1 H).

Stage 2. Synthesis of (1S, 4S, 5R) -1-fluoro-4- (hydroxymethyl) -3-azabicyclo [3.2.0jheptan-2one (L98). To a stirred solution of compound C131 (200 mg, 0.72 mmol) in 9 ml of acetonitrile and 1 ml of water, 4-toluenesulfonic acid (7 mg, 0.04 mmol) was added. The reaction mixture was heated at about 70 ° C for about 1 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L98. Yield: 115 (100%). ¹H NMR (400 MHz, CDCI₃) δ 7.84 (br. s., 1 H), 3.55 - 3.71 (m, 2 H), 3.39 - 3.55 (m, 2 H), 2.81 - 3.00 (m, 1 H), 2.41 - 2.60 (m, 2 H), 2.18 - 2.34 (m, 1 H), 1.36 - 1.53 (m, 1 H).

-167 Preparation 54: (±) - (1S, 5S) -5- (h¡drox¡met¡l) -3-azab¡c¡clof3.1.01hexan-2-one (L100)

OR

<img file="CU20160149A7_D0117.tif" />

/

HO

Stage 1. Synthesis of 1 - ((benzoylloxy) methyl) -3-azabic¡clof3.1.01hexan-3-carboxylate terbutyl (C132) A solution of 1- (hydroxymethyl) - 3-azabicyclo [3.1.0] tert-butyl hexan-3-carboxylate (CAS 161152-76-7, 427 mg, 2 mmol) in DCM (6.4 mL) was treated with benzoic acid (368 mg, 3 mmol), EDCi hydrochloride (581 mg, 3 mmol) and DMAP (49 mg, 0.4 mmol) and heated at about 40 ° C for about 12 h. The mixture was cooled to about 25 ° C, diluted with DCM, washed with 1 M HCI and 10% Na₂CO₃ aqueous. The DCM solution was concentrated, and the residue was purified by chromatography to obtain the title compound C132, which was used in the next step without further characterization. Yield: 0.57 g (90%).

Step 2. Synthesis of 1 - ((benzoyloxy) methyl) -4-oxo-3-azabicyclo [3.1.01hexan-3-carboxylate tert-butyl (C133) A solution of compound C132 (0.57 g , 1.8 mmol) in EtOAc (20 ml) was treated with a solution of sodium periodate (1.5 g, 7.2 mmol) in water (20 ml) and ruthenium trichloride (21 mg (50%), 0.054 mmol). The mixture was stirred at about 20 ° C for about 6 h, then treated with 2-propanol (20 mL) and stirred for about 0.5 h. It was then diluted with water and extracted twice with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C133, which was used in the next step without further characterization. Yield: 0.40 g (60%).

Stage 3. Synthesis of benzoate (4-oxo-3-azab¡c¡clo [3.1.01hexan-1-¡) methanol (C134)

A solution of compound C133 (0.40 g, 0.5 mmol) in DCM (2 mL) was treated with TFA (0.5 mL) and stirred at about 25 ° C for about 15 minutes. The mixture was concentrated, and the residue was re-dissolved in toluene and again concentrated to obtain the title compound C134, which was used in the next step without further characterization.

Step 4. Synthesis of (5- (hydroxymethyl) -3-azabic¡clof3.1.01hexan-2-one (L1Q0) Compound C134 (supposed 0.4 mmol) in THF (2 ml) was treated with NaOH (0, 3 ml of a 2M aqueous solution, 0.6 mmol) and stirred at about 25 ° C for about 1

-168h. This solution of compound L100 was used in the next step without further characterization.

Preparation 55: (±) -3- (hidrox¡metll) octah¡dro-1H-¡so¡ndol-1-one (L101)

<img file="CU20160149A7_D0118.tif" />

Stage 1. Synthesis of (±) -3- (h¡droximetll) octah¡dro-1H-isoindol-1-one (L101). It dissolved

3-oxooctahydro-1H-sodandol-1-ethyl carboxylate (CAS 84385-29-5, 400 mg, 1.9 mmol) in THF (9.5 mL) to which was added borohldride of lithium (59 mg, 2.65 mmoi). The reaction was stirred at about 25 ° C overnight. The mixture was cooled to about 0 ° C, and 2M HCI was added dropwise until gas evolution ceased. The solution was neutralized with K₂CO₃ and leaked. The filtrate was concentrated. The residue was purified by chromatography to obtain the title compound L101. Yield: 0.26 g (81%).¹H NMR (400 MHz, dmso-d₆) Π 4.63 (t, 1 H), 3.42 - 3.50 (m, 1 H), 3.38 - 3.42 (m, 2 H), 2.35 - 2.40 (m, 1 H), 2.23 - 2.30 (m, 1 H), 1.90 - 1.98 (m, 1 H), 1.40-1.63 (m, 3 H), 1.27-1.40 (m, 1 H), 0.84-1.11 (m, 3 H).

Preparation 56: (S) -5- (hydroxymethyl) -5-metylpropyl-2-one (L102)

OR

<img file="CU20160149A7_D0119.tif" />

Step 1. Synthesis of (S) -methyl 2-methyl-5-oxoprolrol-d-2-carboxylate (C135), A solution of (S) -1-butyl-2-methyl 2-met L-5-oxopyrrolldin-1,2-dicarboxylate (CAS 1109790-91-1, 1.2 g, 4.7 mmol) in DCM was treated with TFA (0.36 ml, 4.7 mmol) for about 2 has about 25 ° C. The mixture was concentrated to obtain the title compound C135. Yield: 1.2 g (100%).¹H NMR (400 MHz, CDCI₃) δ

7.78 (br. S., 1 H), 3.80 (s, 3 H), 2.48 - 2.66 (m, 3 H), 2.02 - 2.15 (m, 1 H), 1.58 (s, 3 H). Stage 2. Synthesis of (S) -5- (hydroxymethyl) -5-methylpyrrolin-2-one (L102), A solution of compound C135 (1.2 g, 4.7 mmol) in THF (76 ml) It was treated with lithium borohldride (218 mg, 9.9 mmol). The reaction continued overnight, then the solution was cooled to about 0 ° C, and 2M HCI was added dropwise until gas evolution ceased. The solution was neutralized with K₂CO₃ and leaked. The filtrate was concentrated. The residue was purified by chromatography to obtain the title compound C136 as a

-169 oil that crystallized. It was triturated with ether and filtered to obtain the title compound L.1Q2. Yield: 0.30 g (49%).¹H NMR (400 MHz, dmso-d₆) δ 7.43 (br. s „1

H), 4.83-4.87 (m, 1 H), 3.16 - 3.24 (m, 2 H), 2.06-2.21 (m, 2 H), 1.96 (ddd, 1 H), 1.59 (ddd, 1 H), 1.09 (s, 3 H).

Preparation 57: 5- (h¡drox¡met¡l) -4- (tr¡fluQromet¡l) p¡rrQl¡d¡n-2-one (L104)

<img file="CU20160149A7_D0120.tif" />

Step 1. Synthesis of 2- ((diphenylmethylene) amino) -3- (diethyl trifluoromethyl) pentandóoate (C136). A mixture of 2- ((d-phenylmethylene) amino) ethyl acetate (CAS 69555-14-2, 1.9 g, 7 mmol), benzyltriethylammonium chloride (0.3 g, 1.3 mmol), 10% of aqueous NaOH (10 ml) and DCM (10 ml) was stirred at about 0 ° C for about 15 min. After the addition of 4,4,4-trifluorobut-2-enoate of (E) -ethyl (CAS 25597-16-4, 1 ml, 7 mmol), the mixture was vigorously stirred for about 90 min at about 0 ° C The DCM was separated, and the aqueous phase was extracted with DCM. The combined DCM extracts were washed with brine, dried over MgSO₄, filtered and concentrated to obtain the title compound C136. Yield: 2.6 g (85%).¹H NMR (400 MHz, CDCI₃) δ 7.62 - 7.67 (m, 2 H), 7.43 - 7.50 (m, 4 H), 7.31 - 7.38 (m, 2 H), 7.14 - 7.20 (m, 2 H), 4.43 (d, 1 H), 4.13 - 4.25 (superimposed q, 4 H), 3.62 - 3.74 (m, 1 H), 3.12 (dd, 1 H), 2.81 (dd, 1 H), 1.27 (superimposed t, 6 H).

Step 2. Synthesis of ethyl 5-oxo-3- (trifluoromethyl) pyrrolidin-2-carboxylate (C137), A mixture of compound C136 (2.6 g, 6.0 mmol), 10% acid Aqueous citrus (24 ml, 212 mmol) and THF (17 ml) was stirred at about 25 ° C for 2 days. The reaction was extracted with EtOAc, and the combined EtOAc extracts were washed with brine, dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C137. Yield: 1.1 g (85%).¹H NMR (400 MHz, CDCI₃) δ 6.72 (br. s., 1 H), 4.28 (q, 2 H), 3.40 (m, 1 H), 2.70 (dd, 1 H), 2.52 (dd, 1 H), 1.33 (t, 3 H).

Step 3. Synthesis of 5- (hydroxymethyl) -4- (trifluoromethyl) pyrrolidin-2-one (L104). To a solution of compound C137 (1.1 g, 5.1 mmol) in THF (25 ml), lithium borohydride (0.16 g, 7.1 mmol) was added. The mixture was stirred at about 25 ° C overnight.

The mixture was cooled to about 0 ° C, and 2M HCI was added until gas evolution ceased. The mixture was neutralized with K₂CO₃ and leaked. The filtrate is

-170 concentrated, and the residue was purified by chromatography to obtain the title compound L104. Yield: 0.44 g (47%).¹H NMR (400 MHz, dmso-d₆) δ 7.92 (br. s., 1 H, diastereomer 1), 6.89 (d, 1 H, diastereomer 2), 5.35 (m, 1 H, diastereomer 2), 5.07 (t, 1 H, diastereomer 1), 3.84 (m, 1 H, diastereomer 2), 3.58 (m, 1 H, diastereomer 1), 3.30 - 3.46 (m, 3 H, mixture of 1 H diastereomer 1 and 2 H diastereomer 2), 3.12 (m, 1 H, diastereomer 1), 2.74 (dd, 1 H, diastereomer 2),

2.59 (dd, 1 H, diastereomer 1), 2.42 (dd, 1 H, diastereomer 2), 2.17 (dd, 1 H, diastereomer 1).

Preparation 58: (±) - ((1R, 6S) -3-benzyl-3-azabiciclof4.1.01heptan-1-yl) methanol (L105)

<img file="CU20160149A7_D0121.tif" />

Stage 1, Synthesis of (±) - ((1R, 6S) -3-benzyl-3-azab¡c¡clof4.1.01heptan-1-yl) methanol (L105).

In order to obtain the desired target material, (1-benzyl-1,2,5,6-tetrahydropyridin-3-yl) methanol (CAS 244267-39-8, 545 mg, 2.7 mmol)) is cyclopropaned as described in Tetrahedron 2003, 59, 6363 to obtain the title compound L105. Yield: 252 mg (43%).¹H NMR (400 MHz, dmso-d₆) δ 7.13 - 7.41 (m, 5 H), 4.42 (t, 1 H), 3.32 - 3.49 (m, 2 H), 3.28 (dd, 1 H), 3.08 (dd, 1 H), 2.74 (d, 1 H), 2.21 - 2.39 (m, 2 H), 1.77 - 1.98 (m, 2 H), 1.49 - 1.70 (m, 1 H), 0.69 - 0.85 (m, 1 H), 0.39 - 0.53 (m, 2 H).

Preparation 59: (S) -4- (hydroxymethyl) -1-methylimidazoline-2-one (L106)

OR

Λ

HN N

HO— &lt;

Step 1. Synthesis of (S) -l-benzyl 5-methyl 2-oxoimdadazine-1,5-dicarboxylate (C138).

To a suspension of (S) -3 - ((benzyloxy) carbonyl) -2-oxoimidazolidin-4-carboxylic acid (CAS 59760-01-9, 3.0 g, 11.4 mmol) in MeOH (40 ml), thionyl chloride (0.4 ml, 5.7 mmol) was added slowly at about 25 ° C. The mixture was stirred at about 25 ° C overnight before the volatiles were removed under reduced pressure. The residue was dissolved in DCM, and the DCM was washed with NaHCO₃ saturated aqueous. The DCM was dried in MgSO₄, filtered and concentrated to obtain the title compound C138.

Yield: 2.9 g (93%). ¹H NMR (400 MHz, dmso-d₆) δ 7.26 - 7.45 (m, 5 H), 5.19 -171 (q, 2 Η), 4.78 (dd, Hz, 1 H), 3.66 (s, 3 H), 3.63 - 3.71 (m, 1 H), 3.37 (dd, 1 H), 2.71 (s, 3 H).

Step 2. Synthesis of (S) -1-benzyl 5-methyl 3-methyl-2-oxoimidazoline-1,5-dicarboxylate (C139). To a solution of compound C138 (0.96 g, 3.5 mmol) in DME (17 mL), K was added₂CO₃ (0.96 g, 6.9 mmol) and then iodomethane (0.87 ml, 13.9 mmol). The mixture was heated at about 50 ° C for about 19 h. The mixture was then cooled to about 25 ° C and diluted with water. The layers were separated, and the aqueous phase was extracted three times with EtOAc. The combined DME and EtOAc extracts were washed with NH₄Semisaturated aqueous CI, brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C139. Yield: 0.75 g (74%).¹H NMR (400 MHz, dmso-d₆) δ 7.31 - 7.44 (m, 5 H), 5.19 (dd, 2 H), 4.78 (dd, 1 H), 3.67 - 3.74 (m, 1 H), 3.37 (dd, 1 H), 3.31 (s, 2 H), 2.71 (s, 3 H).

Step 3. Synthesis of (S) benzyl (C140) 5- (hydroxymethyl) -3-methyl-2-oxoimidazolidin-1-carboxylate (C140). NaBH was slowly added₄ (119 mg, 3.1 mmol) to the solution of compound C139 (0.75 g, 2.6 mmol) in EtOH (7 mL) at about 0 ° C. The mixture was stirred at about 0 ° C for about 2.5 h, at which time 119 mg of NaBH was added.₄ additional. Stirring was continued at about 0 ° C for approximately 1.5 h more. Hydrochloric acid (10%) was added dropwise to the cooled mixture until gas evolution ceased. The mixture was concentrated under reduced pressure, and the residue was absorbed in EtOAc. The EtOAc extract was washed with saturated aqueous NaHCOs, water, brine, dried over Na₂SW_4l filtered and concentrated to obtain the title compound C140. Yield: 200 mg (30%).¹H NMR (400 MHz, dmso-d₆) δ 7.24 - 7.49 (m, 5 H), 5.10 - 5.28 (m, 2 H), 5.02 (t, 1 H), 4.04 - 4.19 (m, 1 H), 3.42 - 3.60 (m, 2 H), 3.25 (dd, 1 H), 2.71 (s, 3 H).

Step 4. Synthesis of (S) -4- (hydroxymethyl) -1-methylimidazole-2-one To a solution of compound C140 (200 mg, 0.74 mmol) in MeOH (19 mL), Palladium on carbon (25 mg) was added, and the mixture was stirred under a hydrogen atmosphere (1 atm) for about 6 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography to obtain the title compound L106. Yield: 61 mg (64%).¹H NMR (400 MHz, dmso-d₆) δ 3.46-3.55 (m, 1 H), 3.31-3.38 (m, 2 H),

3.24-3.31 (m, 1 H), 3.05 (dd, 1 H), 2.59 (s, 3 H).

Preparation 60: 1-benzyl-6-hydrox-1-azaspiro [4.4lnonan-2-one (Ll 07)

-172-

<img file="CU20160149A7_D0122.tif" />

\ / YH

Step 1. Synthesis of 1-benzyl-1H-pyrrol-2 (5H) -one (C141), A mixture of 2,5-dimethoxy2,5-dihydrofuran (12.2 ml, 100 mmol), N -benzylamine (10.9 ml, 100 mmol), concentrated HCI (12.5 ml, 150 mmol) and H₂Or (400 ml) was stirred for about 5 h at about 25 ° C. The mixture was neutralized with NaHCO₃ solid and extracted with EtOAc. The EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C141. Yield: 5.0 g (29%).¹H NMR (400 MHz, CDCI₃) δ 7.26 - 7.38 (m, 5 H),

6.33-6.36 (m, 1 H), 5.29-5.32 (m, 1 H), 4.65 (s, 2 H), 3.14-3.15 (m, 2 H).

Step 2, Synthesis of 1-benzyl-2 - ((tert-butyldimethylsilyl) oxy) -1H-pyrrole (C142), To a solution of compound C141 (2.0 g, 12 mmol) and Et₃N (3.3 ml, 23 mmol) in anhydrous DCM (20 ml), t-butyldimethylsilyl triflate (2.4 ml, 12 mmol) was added at about 25 ° C. After about 5 h, the reaction mixture was diluted with EtOAc and H₂O. The aqueous phase was separated and extracted with EtOAc. The combined EtOAc extracts were washed with NaHCO₃ saturated aqueous and concentrated. The residue was purified by chromatography to obtain the title compound C142. Yield: 2.0 g (61%).¹H NMR (400 MHz, CDCI₃) δ 7.10 - 7.15 (m, 4 H), 6.90 6.93 (m, 1 H), 6.03 - 6.04 (m, 1 H), 5.78 - 5.80 (m, 1 H), 5.07 - 5.09 (m, 1 H) , 4.76 (s, 2 H), 0.073 (s, 9 H), 0.00 (s, 6 H).

Step 3. Synthesis of 1-benzyl-5- (1-hydroxycclobutyl) -1H-pyrrole-2 (5H) -one (C143), To a solution of compound C142 (500 mg, 1.7 mmol) in DCM (12 ml) at 25 ° C, 3 A molecular sieves and cyclobutanone (0.21 ml, 2.8 mmol) were added. The resulting mixture was stirred for about 15 min at about 25 ° C and then cooled to about -78 ° C. BF drip added₃-Et₂O (0.32 ml, 370 mg, 2.6 mmol). The mixture was stirred at about -78 ° C for about 2 h, then heated to about 0 ° C and quenched with H₂O. The DCM was separated, washed with NaHCO₃saturated aqueous, and the aqueous phase was extracted with DCM. DCM extracts were washed with NaHCO₃ saturated, dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound.

-173C143. Yield: 300 mg (71%).¹H NMR (300 MHz, CDCI₃) δ 7.09 - 7.24 (m, 5 H),

6.90 - 6.92 (m, 1 H), 6.23 - 6.25 (m, 1 H), 5.00 (d, 1 H), 4.27 (d, 1 H), 4.05 - 4.06 (m, 1 H), 2.21 - 2.23 ( m, 1 H), 1.95 - 2.04 (m, 2 H), 1.82 - 1.86 (m, 2 H), 1.81 (s, 1 H),

1.42-1.49 (m, 1 H).

Stage 4. Synthesis of 1-benzyl-1-azaspiro [4.4jnonan-2,6-dione (C144). To a solution of compound C143 (300 mg, 1.2 mmol) in DCM (20 ml) at 0 ° C, concentrated HCI (0.2 ml, 2.2 mmol) was added. The mixture was stirred at about 0 ° C for about 5 h and concentrated to obtain compound C144 that was used without purification.¹H NMR (400 MHz, CDCI₃) δ 7.06 - 7.30 (m, 5 H), 4.75 (d, 1 H), 3.90 (d, 1 H), 2.37 - 2.59 (m, 2 H), 2.21 - 2.37 (m, 1 H), 1.99 - 2.10 (m, 1 H), 1.83 - 1.99 (m, 3 H),

1.58-1.83 (m, 3 H).

Stage 5. Synthesis of 1-benzyl-6-hydroxy-1-azaspirof4.41nonan-2-one (L107). NaBH was added₄ (38 mg, 0.93 mmol) to a solution of compound C144 (150 mg, 0.62 mmol) in MeOH (4 ml). The mixture was stirred at about 25 ° C for about 20 min before it was diluted with H₂Or and extracted with EtOAc. The combined EtOAc extracts were washed with water and brine, dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound L107 as a mixture of diastereomers. Yield: 105 mg (70%). It was used in the next stage without further characterization.

Preparation 61: (S) -4- (hydroxymethyl) imdadazolidin-2-one (L108)

Or χ

HN NH

HO— '

Step 1. Synthesis of methyl (4S) -2-oxoimidazolidin-4-carboxylate (0145). A suspension of 1-benzyl 5-methyl (5S) -2-oxoamidazolidin-1,5-dicarboxylate (CAS 16839908-4, 325 mg, 1.2 mmol) and 10% Pd / C (33 mg ) in MeOH (4.7 ml) was stirred under a hydrogen atmosphere at about 25 ° C for about 5.5 h. The mixture was filtered and concentrated to obtain the title compound 0145. Yield: 163 mg (97%).¹H NMR (400 MHz, dmso-d₆) δ 6.73 (s, 1 H), 6.34 (s, 1 H), 4.25 (ddd, 1 H),

3.52 - 3.65 (m, 2 H), 3.32 (2, 3 H).

Stage 2. Synthesis of (4S) -4- (hydroxymethyl) imidazolidin-2-one (L108). Sodium borohydride (56 mg, 1.4 mmol) was added to a solution of compound C145 (160 mg,

1.1 mmol) at about 0 ° C. The mixture was stirred at about 0 ° C for

-174 about 3 hours, and then 10% HCI solution was added drip until gas evolution ceased. The mixture was concentrated, and the residue was diluted with EtOAc. The EtOAc was washed with NaHCO₃ saturated aqueous, brine, dried over Na₂SW₄, filtered and concentrated to obtain the title compound L108. Yield: 360 mg (a mixture of the desired product and salts), It was used in the next step without purification,¹H NMR (400 MHz, dmso-d₆) δ 3.53 - 3.61 (m, 1 H), 3.30 - 3.36 (m, 2 H), 3.23 - 3.30 (m, 1 H), 3.04 (dd, 1 H).

Preparation 62: (3S, 3aR, 6aS) -5-benzyl-3- (hydroxymethyl) hexahylpyrrolo [3,4-c1prol1 (2H) -one (L109)

OR

<img file="CU20160149A7_D0123.tif" />

Stage 1. Synthesis of (5aS, 8aR, 8bS) -7-benzyl-3,3-d¡met¡lhexahydro-1H-polo [3 ', 4': 3,41 pyrolus [1,2 -c1oxazol-5 (3H) -one (C146). A solution of compound P20 (100 mg, 0.65 mmol) in DCM (5 ml) and N- (methoxymethyl) -N - [(trimethylsilyl) methyl] -benzemethanamine (CAS 93102-05-7 , 232 mg, 0.98 mmol) was treated with TFA (0.01 mL, 0.13 mmol) at 0 ° C. The mixture was maintained at about 25 ° C for about 16 h, then heated at about 40 ° C for about 4 h, before an additional 232 mg of CAS 93102-05-7 was added. The heating continued for about 16 h. The reaction mixture was cooled to about 25 ° C, neutralized with Et₃N (18 μΙ, 0.13 mmol) and concentrated. The residue was purified by chromatography to obtain the title compound C146. Yield: 110 mg (59%).¹H NMR (400 MHz, dmso-d₆) δ 7.16 - 7.41 (m, 5 H), 3.98 (dd, 1 H), 3.78 - 3.87 (m, 1 H), 3.59 - 3.68 (m, 1 H), 3.48 3.58 (m, 1 H), 3.35 (dd, 1 H), 3.10 (t, 1 H), 2.95 (d, 1 H), 2.79 (d, 1 H), 2.56 - 2.66 (m, 1 H), 2.24 (t, 1 H), 2.18 (dd, 1 H), 1.53 (s, 3 H), 1.33 (s, 3 H).

Stage 2, Synthesis of (3S, 3aR, 6aS) -5-benzyl-3- (hydroxymethyl) hexahydropyrrolof3,4-c1prol1 (2H) -one (L109). To a stirred solution of compound C5146 (110 mg, 0.38 mmol) in 6 ml of acetonitrile and 0.6 ml of water, TFA (36 μΙ, 0.46 mmol) was added. The reaction mixture was heated at about 60 ° C for about 2 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L109. Yield: 60 mg (64%). ¹H NMR (400 MHz, CD₃OD) δ 7.20 - 7.37 (m, 5 H), 3.61 (s, 2 H), 3.46 - 3.55 (m, 2 H),

-1753.39 - 3.45 (m, 1 Η), 2.92 - 3.02 (m, 2 Η), 2.66 - 2.78 (m, 2 Η), 2.57 (dd, 1 Η), 2.45 2.53 (m, 1 Η).

Preparation 63: 2 - ((5S) -5- (hydroxymethyl) -2-oxopyrrolidin-3-yl) acetonitrile (L110)

<img file="CU20160149A7_D0124.tif" />

Stage 1: Synthesis of 5 - (((tert-butoxycarbonyl) oxy) methyl) -3- (cyanomethyl) -2-oxopyrrolidine-1-carboxylate of (5S) -ter-butyl (C147). LDA solution (2M, 2.4 ml) was added to a solution of 2- (((tert-butoxycarbonyl) -oxy) methyl) -5-oxoprolrolin-1-carboxylate of (S) -butyl (CAS 360782-62-3, 1.0 g, 3.2 mmol) in THF (20 ml) at about -78 ° C. After about 30 min, bromoacetonitrile (0.22 ml, 3.2 mmol) was added. The mixture was stirred at about -78 ° C for about 20 min, and then NaHCO was added.₃ saturated aqueous (2 ml). The mixture was diluted with H₂O and extracted with EtOAc. The combined EtOAc extracts were washed with H₂Or, brine, dried over MgSO₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C147. Yield: 0.86 g (77%).¹H NMR (400 MHz, CDCI₃) δ 4.50 (dd, 1 H), 4.36 - 4.44 (m, 1 H), 4.10 - 4.19 (m, 1 H), 3.08 - 3.22 (m, 1 H), 2.88 (dd, 1 H), 2.60 ( dd, 1 H), 2.41 (dd, 1 H), 2.06-2.20 (m, 1 H), 1.53 - 1.62 (m, 18 H).

Stage 2. Synthesis of 2 - ((5S) -5- (hydroxymethyl) -2-oxopyrrol¡d¡n-3-¡) acetonitrile (L110). Concentrated HCI (2 mL) was added to a solution of compound C147 (500 mg, 1.4 mmol) in MeOH (5 mL) and DCM (5 mL). The mixture was stirred at about 25 ° C overnight, then concentrated to obtain the title compound L110.¹H NMR (400 MHz, CD₃OD) δ 3.76 - 3.67 (m, 1 H), 3.56 - 3.48 (m, 2 H), 2.90 - 2.87 (m, 1 H), 2.73 2.65 (m, 2 H), 2.27 - 2.24 (m, 1 H ), 2.12 - 2.05 (m, 1 H).

Preparation 64: 1- (hydroxymethyl) -3-oxotetrahydropyrrolof3,4-cjpirrol-2,5 (1 H, 3H) dicarboxylate (1S, 3aS, 6aR) -di-tert-butyl (LUI)

-176-

<img file="CU20160149A7_D0125.tif" />

Step_1, _Synthesis_of_5-benzyl-1 - (((tert-butyldimethylsilyl) oxy) methyl) -3oxohexahydropyroloyl3,4-c1prrol-2 (1H) -carboxylate (1S, 3aS, 6aR) -ter-butyl (C148).

A solution of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -5-oxo-2,5-dihydro-1 H-pyrrole-1 carboxylate of (S) -ter-butyl (CAS 81658-27- 7, 3.0 g, 9.2 mmol) and N- (methoxymethyl) -N [(trimethylsilyl) methyl] -benzenemethanamine (CAS 9310-05-7, 3.27 g, 13.8 ) in DCM (80 ml) was treated with TFA (208 mg, 1.84 mmol) at about 25 ° C and held for about 18 h. Triethylamine (0.26 mL, 1.84 mmol) was added and the mixture was concentrated. The residue was purified by chromatography to obtain the title compound C148. Yield: 2.6 g (61%).¹H NMR (400 MHz, dmso-d₆) δ 7.27 - 7.34 (m, 2 H), 7.19 - 7.27 (m, 3 H), 3.87 - 3.91 (m, 1 H), 3.84 (dd, 1 H), 3.65 (d, 1 H), 3.53 ( s, 2 H), 2.90 - 2.97 (m, 1 H), 2.82 - 2.89 (m, 1 H), 2.65 - 2.73 (m, 2 H), 2.54 - 2.63 (m, 2 H), 1.45 (s, 9 H), 0.82 (s, 9 H), 0.01 (s, 3 H), -0.02 (s, 3 H)

Stage 2: Synthesis of 1 - (((tert-butyldimethylsilyl) oxy) methyl) -3-oxotetrahydropyrrolof3,4-c1prol2,5 (1 H, 3H) -dicarboxylate of (1S, 3aS, 6aR) -d-tert-butyl (C149). To a solution of compound C148 (2.2 g, 4.8 mmol) and di-t-butyl dicarbonate (3.1 g, 14.4 mmol) in MeOH (150 ml), palladium on carbon (200 mg), and the mixture was stirred under a hydrogen atmosphere (1 atm) for about 18 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography to obtain the title compound C149. Yield: 1.12 g (49%).¹H NMR (400 MHz, CD₃OD) δ

3.99 - 4.10 (m, 2 H), 3.68 - 3.88 (m, 4 H), 3.45 - 3.55 (m, 1 H), 3.11 (dd, 1 H), 2.87 2.99 (m, 1 H), 1.54 (s , 9 H), 1.45 (s, 9 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H). Stage 3. Synthesis of 1- (hydroxymethyl) -3-oxotetrahydropyrrolof3,4-c1prrol-2,5 (1H, 3H) dicarboxylate (1S, 3aS, 6aR) -di-ter-butyl (L111 ). A solution of compound C149 (1.22 g, 2.6 mmol) in THF (100 mL) was treated with tetrabutylammonium fluoride (1 M, 3.9 mL) at about 25 ° C. After about 2 h, the mixture was concentrated. The residue was purified by chromatography to obtain the title compound L111.

Yield: 600 mg (65%). ¹H NMR (400 MHz, CD₃OD) δ 4.18 (dd, 1 H), 4.05 (dd, 1

H), 3.69 - 3.82 (m, 2 H), 3.56 - 3.69 (m, 1 H), 3.47 (dd, 1 H), 3.21 (dd, 1 H), 3.08 - 3.17 (m, 1 H), 2.87 -2.99 (m, 1 H), 1.46 (s, 9 H), 1.46 (s, 9 H)

-177 Preparation 65: (4R, 5S) -4- (hydroxymethyl) -5-methioxazolidine-2-one (L112)

HO

HN

Λ '0

<img file="CU20160149A7_D0126.tif" />

Stage 1, Synthesis of (4R, 5S) -4- (hydroxymethyl) -5-methylxazolidin-2-one (L112). To a mixture of 5-methyl-2-oxooxazolidine-4-carboxylate (4S, 5S) -methyl (CAS 182267-22-7, 165 mg, 1.0 mmol) in EtOH (6 ml) at around 0 ° C, NaBH was added₄ (43 mg, 1.1 mmol). After the evolution of gas ceased, the mixture was stirred at about 25 ° C for about 4 h. The mixture was cooled again to about 0 ° C and NaBH was added.₄ additional (35 mg, 0.9 mmol). The mixture was heated to about 25 ° C, and after about 2 h, NH was added.₄Saturated aqueous CI, and the mixture was stirred overnight. The mixture was filtered, and the solids were washed with EtOH. The filtrate was concentrated, and the residue was purified by chromatography to obtain the title compound L112. Yield: 97 mg (72%).¹H NMR (400 MHz, CDCI₃) Π

6.72 (s, 1 H), 4.72 - 4.88 (m, 1 H), 3.99 (br. S., 1 H), 3.74 - 3.86 (m, 1 H), 3.54 - 3.73 (m, 2 H), 1.38 (d, 3 H).

Preparation 66: (1S, 4S, 5R) -4- (h¡drox¡met¡l) -3-azab¡cíclof3.1.0lhexan-2-one (L113)

HO

OR

<img file="CU20160149A7_D0127.tif" />

H

Stage 1. Synthesis of (5aS, 6aR, 6bS) -3,3-d¡met¡ltetrah¡dro-1H-c¡clopropaf3,4] pyrrolof1,2cíoxazol-5 (3H) -one (C150). A solution of compound P20 (1.0 g, 6.5 mmol) in DCM (40 ml) was cooled to 0 ° C, and a solution of diazomethane (prepared from

6.7 g of N-methyl-N-nitrosurea in 65 ml of diethyl ether). Palladium acetate (72 mg, 0.32 mmol) was added in portions at about 0 ° C. The mixture was heated at about 25 ° C for about 16 h. The mixture was filtered, and a second portion of diazomethane and palladium acetate was added and stirred overnight. The addition of diazomethane and palladium acetate was repeated two more times. The mixture was filtered, and the filtrate was concentrated. The residue was purified by HPLC to obtain the C150 title compound. Yield: 100 mg (9%).¹H NMR (400 MHz, CD₃OD) δ

-1783.47-3.57 (m, 3Η), 1.90 - 1.98 (m, 1 H), 1.75-1.81 (m, 1 H), 1.12-1.19 (m, 1 H), 0.58-0.63 (m, 1 H).

Stage 2. Synthesis of (1S, 4S, 5R) -4- (hydroxymethyl) -3-azabicyclo [3.1.0lhexan-2-one (L113).

To a stirred solution of compound C150 (95 mg, 0.57 mmol) in 5 ml of acetonitrile and 1 ml of water, 4-toluenesulfonic acid (5 mg, 0.03 mmol) was added. The reaction mixture was heated at about 90 ° C for about 1 h. The reaction mixture was cooled to about 25 ° C, concentrated, and the residue was purified by chromatography to obtain the title compound L113. Yield: 35 mg (33%).¹H NMR (400 MHz, CD₃OD) δ 4.61 (br. S, 1 H), 3.95 (d, 1 H), 3.65 (dd, 1 H), 3.51 (dd, 1 H), 3.34 (dt, 1 H), 2.01 - 2.10 (m , 1 H), 0.98 - 1.05 (m, 1 H), 0.78 - 0.83 (m, 1 H).

Preparation 67: 6,6-dichloro-2- (hydroxymethyl) -4-oxo-3-azabicyclo [3.1.Ojhexan-3-carboxylate of (1S, 2S, 5R) -ter-butyl (L114)

<img file="CU20160149A7_D0128.tif" />

Step 1._Synthesis of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -6,6-dichloro-3azabicyclo-3.1.01hexan-3-carboxylate of (1S, 2S, 5R) -ter-butyl (C151). To a stirred solution of (S) tert-butyl 2 - (((tert-butyldimethylsilyl) oxy) methyl) -2,5-dihydro-1 H-pyrrol-1-carboxylate (CAS 247200-49-3, 5, 0 g, 16 mmol) and benzyltriethylammonium chloride (0.73 g,

3.2 mmol) in CHCI₃ (100 ml), 50% NaOH solution (100 ml) was added. The mixture was stirred at about 25 ° C for about 16 h, then diluted with DCM and separated. The aqueous phase was extracted twice with additional DCM. The combined DCM extracts were washed with water, brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C151. Yield: 3.6 g (57%) as a colorless liquid.¹H NMR (400 MHz, CDCI₃) δ 3.90 - 4.09 (m, 1 H), 3.81 - 3.89 (m, 1 H), 3.73 3.81 (m, 1 H), 3.61 - 3.73 (m, 1 H), 3.57 (dd, 1 H), 2.28 - 2.39 (m, 1 H), 2.22 - 2.29 (m, 1 H), 1.43 (d, 9 H), 0.90 (d, 9 H), 0.03 - 0.10 (m, 6 H)

Step 2. Synthesis of 2 - (((tert-butyldimethylsilyl) oxy) methyl) -6,6-dichloro-4-oxo-3azabicyclic 3.1.0jhexan-3-carboxylate of (1S, 2S, 5R) -ter- butyl (C152), Sodium periodate (654 mg, 3.0 mmol) was dissolved in water (6.5 mL), and an amount was added

-179 Catalytic hydrated ruthenium dioxide. After stirring for 5 min, a solution of compound C151 (400 mg, 1.0 mmol) in EtOAc (6.5 ml) was added. The resulting mixture was vigorously stirred overnight. The phases were separated, and the EtOAc phase was washed with sodium bisulfate solution, brine, dried over Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C152. Yield: 290 mg (70%).¹H NMR (400 MHz, CDCIs) δ 4.16 - 4.21 (m, 1 H), 3.92 - 3.98 (m, 1 H), 3.85 - 3.91 (m, 1 H), 2.82 (dd, 1 H), 2.56 (d , 1 H), 1.51 (s, 9 H), 0.89 (s, 9 H), 0.08 (s, 3 H), 0.06 (s, 3 H).

Step 3. Synthesis of 6,6-dichloro-2- (hydroxymethyl) -4-oxo-3-azab¡c¡clof3.t. Ojhexan-3 carboxylate of (1S, 2S, 5R) -ter -butyl (L114), Compound C152 (290 mg, 0.7 mmol) in THF (8 ml) was treated with tetrabutylammonium fluoride (1 M, 1.4 ml) at about 25 ° C. The mixture was stirred at about 25 ° C for about 4 h, then water was added, and the mixture was extracted twice with EtOAc (15 ml each). The combined EtOAc extracts were washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The residue was purified by chromatography to obtain the title compound L114. Yield: 124 mg (59%).¹H NMR (400 MHz, CDCI₃) δ

5.57 (br. S „1 H), 4.19-4.27 (m, 1 H), 4.08-4.15 (m, 1 H), 3.90 (t, 1 H), 2.81 (d, 1 H),

2.55 (d, 1 H), 1.51 (s, 9 H).

Preparation 68: (S) -5 - ((S) -1-hydroxyethyl) pyrrolidin-2-one (LI15)

OR

<img file="CU20160149A7_D0129.tif" />

Stage 1. Synthesis of (S) -5 - ((S) -1-hydroxyethyl) pyrrolidin-2-one (L115). A mixture of (S) 5 - ((S) -1-hydroxyethyl) -1- (9-phenyl-9H-fluoren-9-yl) pyrrolidin-2-one (CAS 191406-21-0, 750 mg, 2 , 0 mmol) and palladium on carbon (350 mg) in MeOH (36 ml) and EtOAc (36 ml) was hydrogenated at about 40 psi for about 30 h at about 25 ° C. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography to obtain the title compound L115. Yield: 220 mg (84%). ¹H NMR (400 MHz, dmso-d₆) δ 7.51 (br. s, 1 H), 4.66 (d, 1 H), 3.41 - 3.45 (m, 1 H),

3.31 -3.36 (m, 1 H), 2.08-2.13 (m, 2 H), 1.93-2.05 (m, 1 H), 1.62 - 1.70 (m, 1 H), 0.98 (d, 3 H).

-180 Preparation 69: (4S, 5S) -4- (2-fluoroethyl) -5- (h¡drox¡metil) p¡rrol¡d¡n-2-one (L116) Stage 1. Synthesis of (7R, 7aS ) -7- (2-h¡drox¡etiQ-3.3-d¡met¡ltetrah¡drop¡rroloí1,2-c1oxazol5 (3H) -ona (C153). Cyclohexene (4.3 mi, 42 mmol) was added to a solution of borane in THF (1 M, 21.1 ml) at about 0 ° C. After 30 min, the mixture was heated to about 25 ° C and stirred for an additional 30 min. After cooling to about 0 ° C, a solution of compound C55 (2.55 g, 14.1 mmol) in DCM (70 mL) was added dropwise over about 15 min. After about 90 minutes at 0 ° C, water (40 ml) was added, and the mixture was stirred for about 30 min at about 0 ° C. The mixture was partially concentrated to remove about 50 ml of DCM, and THF (20 ml) was added. Sodium perborate tetrahydrate (8.93 g, 56 mmol) was added, and the mixture was stirred overnight, while heating at about 20 ° C. The phases were separated, and the aqueous phase was extracted 5 times with DCM and 3 times with MTBE. The combined DCM and MTBE extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C153. Yield: 2.04 g (73%).¹H NMR (400 MHz, CDCI₃) δ 4.38 (dt, 1 H), 3.91 (dd, 1 H), 3.68 - 3.77 (m, 2 Η), 3.60 - 3.68 (m, 1 H), 2.94 (dd, 1 H), 2.53 - 2.65 ( m, 1 Η), 2.34 (dd, 1 H), 1.71-1.82 (m, 1 H), 1.65 (s, 3 H), 1.51 -1.62 (m, 2 H), 1.48 (s, 3 H).

Step 2. Synthesis of (7S, 7aS) -7- (2-fluoroethyl) -3,3-dimethyltetrahydropyrrolo [1,2-c1oxazol5 (3H) -one (C154). To a solution of compound C153 (1.43 g, 7.2 mmol) in DCM (36 mL) at about 0 ° C, 2,6-lutidine (2.09 mL, 17.9 mmol), DAST was added (1.75 ml, 14.4 mmol) and triethylamine trihydrofluoride (1.16 ml, 7.2 mmol). The mixture was stirred overnight while heating to about 20 ° C, then added dropwise to NaHCO.₃ saturated aqueous. The mixture was extracted 4 times with DCM. The combined DCM extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C154. Yield: 1.06 g (73%).¹H NMR (400 MHz, CD3OD) δ 4.55 - 4.52 (m, 1 H), 4.47 - 4.40 (m, 2 H), 3.92 (dd, 1 H), 3.78 - 3.73 (m, 1 H), 2.99 (dd , 1 H), 2.66 - 2.58 (m, 1 H), 2.36 (dd, 1 H), 2.01 -1.86 (m, 1 H), 1.74-1.61 (m, 1 H), 1.60 (s, 3 H) , 1.44 (s, 3 H). ¹⁹F NMR (376 MHz, CD3OD) δ -221.50.

Step 3. Synthesis of 4S, 5S) -4- (2-fluoroethyl) -5- (hydroxymethylProlrolin-2-one (L116). To a stirred solution of compound C154 (130 mg, 0.65 mmol) in 6 , 5 ml of -181acetonitrile and 1.3 ml of water, TFA (5 ul, 0.07 mmol) was added.The reaction mixture was heated at about 90 ° C for about 1 h.The reaction mixture was cooled to about 25 ° C, concentrated, then re-dissolved twice in acetonitrile and water, and concentrated to obtain the title compound L116. Yield: 90 mg (86%). ¹H NMR (400 MHz, CD3OD) δ 4.63 - 4.51 (m, 1 H), 4.51 4.37 (m, 1 H), 3.70 - 3.57 (m, 3 H), 2.72 (m, 1 H), 2.38 - 2.18 ( m, 2 H), 2.14-1.95 (m, 1 H), 1.95 - 1.73 (m, 1 H). ¹⁹F NMR (376MHz, CD3OD) δ -220.91.

Preparation 70: (4R, 5S) -4- (fluorometll) -5- (hydroxymethyl) pyrrolidin-2-one (L117)

<img file="CU20160149A7_D0130.tif" />

Step 1. Synthesis of (7R, 7aS) -7- (1,2-d! Hydroxyethyl) -3,3-dimethyltetrahydropyrrolof1,2c1oxazol-5 (3H) -one (C155). To a solution of compound C55 (1.50 g, 8.3 mmol) in acetone (30 ml) and H₂O (3 ml), N-methylmorpholin-N-oxide (1.38 g, 11.8 mmol) and then osmium tetroxide (31 mg, 0.12 mmol) was added at about 25 ° C. The mixture was stirred at about 25 ° C for about 3 h, then concentrated. The residue was purified by chromatography to obtain the title compound C155 as a mixture of two diastereomers. Yield: 1.47 g (82%).

Stage 2. Synthesis of (7R, 7aS) -7- (h¡drox¡met¡l) -3,3-d¡met¡ltetrah¡dropirrolof1,2-cloxazol5 (3H) -ona (C156). To a solution of compound C155 (2.00 g, 9.3 mmol) in MeCN (50 mL), water (5 mL) was added and then sodium periodate (2.19 g, 10.2 mmol) at about 25 ° C The mixture was stirred at about 25 ° C for 1 h, then cooled to about 0 ° C, treated with NaBH₄ (538 mg, 13.9 mmol) and stirred for about 1 h. The mixture was filtered, concentrated, and the residue was absorbed in DCM and filtered. The filtrate was concentrated to obtain the title compound C156. Yield: 1.69 g (98%).¹H NMR (400 MHz, CD₃OD) δ 4.43 (td, 1 H), 3.98 - 3.84 (m, 2 H), 3.63 - 3.48 (m, 2 H), 2.98 (dd, 1 H), 2.59 -2.49 (m, 1 H), 2.27 (dd, 1 H), 1.59 (s, 3 H), 1.43 (s, 3 H).

Stage 3. Synthesis of (7R_l7aS) -7- (fluoromethyl) -3,3-d¡met¡ltetrah¡drop¡rrolof1,2-e1oxazol5 (3H) -one (C157). To a solution of compound C156 (1.70 g, 9.3 mmol) in DCM (20 mL) at about 0 ° C, 2,6-lutidine (2.7 mL, 23 mmol), DAST (2 , 3 mi,

18.6 mmol) and triethylamine trihydrofluoride (1.5 ml, 9.3 mmol). The mixture was stirred at

-182 around 25 ° C for about 18 h. The reaction was quenched with NaHCO₃saturated aqueous and extracted with DCM. The combined DCM extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C157. Yield: 800 mg (46%).¹H NMR (400 MHz, CDCI3) δ 4.34 - 4.63 (m, 3 H), 4.01 (dd, 1 H), 3.79 - 3.87 (m, 1 H), 3.03 (ddd, 1 H), 2.72 - 2.85 (m , 1 H), 2.26 (dd, 1 H), 1.67 (s, 3 H), 1.51 (s, 3 H). ¹⁹F NMR (376 MHz, CDCI3) δ -218.27.

Step 4. Synthesis of (4R, 5S) -4- (fluoromethyl) -5- (hydroxymethyl) pyrrolidin-2-one (L117). To a stirred solution of compound C157 (87 mg, 0.46 mmol) in 4 ml of acetonitrile and 1 ml of water, TFA (0.1 ml, 1.4 mmol) was added. The reaction mixture was heated at about 90 ° C for about 1 h. The reaction mixture was cooled to about 25 ° C, filtered, concentrated, then re-dissolved in MeOH and toluene and concentrated. The residue was dissolved in MeOH and toluene, and concentrated several more times to obtain the title compound L117. Yield: 57 mg (83%).¹H NMR (400 MHz, CD3OD) δ 4.47 - 4.75 (m, 2 H), 3.73 - 3.82 (m, 1 H), 3.58 3.73 (m, 2 H), 2.96 (td, 1 H), 2.31 (qd, 2 H). ¹⁹F NMR (376 MHz, CD3OD) δ -222.48.

Preparation 71: (3S, 4R, 5S) -3-fluoro-4- (fluoromethyl) -5- (hydroxymethyl) pyrrolidine-2-one (L118)

Step_1_Synthesis_of_ (6S, 7R, 7aS) -6 ~ fluoro-7- (fluoromethyl) -3,3dimethyltetrahydropyrrolol'1,2-cjoxazol-5 (3H) -one (C158), A solution of compound C157 (730 mg, 3.9 mmol) in THF (20 ml) was slowly treated with LDA (2 M, 2.9 ml) at 78 ° C. After 30 min at -78 ° C, a previously cooled solution (-78 ° C) of NFSI (1.97 g, 6.2 mmol) in THF (20 ml) was added by a cannula. Immediately after the addition of NFSI was completed, the reaction was quenched with water at -78 ° C and heated to 25 ° C. The solution was diluted with added water! (15 ml) and extracted with MTBE (50 ml). The aqueous phase was extracted again with MTBE (50 ml), and the combined MTBE extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C158. Yield: 120 mg (15%).¹H NMR (400 MHz, CDCI3) δ 5.36 (dd, 1 H), 4.78 4.65 (m, 1 H), 4.65 - 4.53 (m, 1 H), 4.17 - 4.04 (m, 2 H), 3.96 - 3.86 ( m, 1 H), 3.28 3.08 (m, 1 H), 1.69 (s, 3 H), 1.50 (s, 3 H). ¹⁹F NMR (376 MHz, CDCI3) δ -202.40, 228.51. Also obtained (6R, 7R, 7aS) -6-fluoro-7- (fluoromethyl) -3,3-183 dimethyltetrahydropylIo- [1,2-c] oxazol-5 (3H) -one (C159). Yield: 540 mg (68%).¹H NMR (400 MHz, CDCI3) δ 4.95 (dd, 1 H), 4.65 (d, 1 H), 4.50 - 4.58 (m, 2 H), 4.04 (ddd, 1 H), 3.75 (ddd, 1 H) , 2.76 -2.96 (m, 1 H), 1.65 (s, 3 H), 1.54 (s, 3 H). ¹⁹F NMR (376 MHz, CDCI3) δ -187.58, -223.88.

Stage 2. Epimerization of (6R, 7R, 7aS) -6-fluoro-7- (fluoromethyl) -3,3d¡met¡ltetrahldropirrolo-f1,2-cjoxazol-5 (3H) -one (C159). LDA (2 M, 0.89 ml) was added to a solution of compound C159 (240 mg, 1.2 mmol) in toluene (3 ml) at -78 ° C. The mixture was stirred for 30 min, after which a solution of BHT at 78 ° C (517 mg, 2.3 mmol) in toluene (6 ml) was added. Immediately after the addition of BHT, water (2 ml) was added, and the mixture was heated to 20 ° C. EtOAc was added, and the aqueous phase was extracted again with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain compound C158. Yield: 113 mg (47%).

Stage 3. Synthesis of (3S, 4R, 5S) -3-fluoro-4- (fluoromethyl) -5- (hydroxymethyl) pyrrolidin-2-one (L118). To a stirred solution of compound C158 (370 mg, 1.8 mmol) in 12 ml of acetonitrile and 3 ml of water, silica-bound 4-toluenesulfonic acid (132 mg, 0.09 mmol) was added. The reaction mixture was heated at 80 ° C for 2 h. The reaction mixture was cooled to 25 ° C and concentrated to obtain the title compound L118. Yield: 250 mg (84%).¹H NMR (400 MHz, CD3OD) δ 5.03 (dd, 1 H), 4.81 - 4.74 (m, 1 H), 4.74 - 4.61 (m, 1 H), 3.86 - 3.77 (m, 1 H), 3.69 (dd, 1 H), 3.61 (dd, 1 H), 3.15 2.94 (m, 1 H).¹⁹F NMR (376 MHz, CD3OD) δ -203.74, -227.31.

Preparation 72: (3S, 4S, 5S) -3-fluoro-4- (2-fluoroethyl) -5- (hydroxymethyl) pyrrolidine-2-one (L121)

Stage_T_Synthesis_of_ (6S, 7S, 7aS) -6-fluoro-7- (2-fluoroethyl) -3,3dimethyltetrah I d ro pi rrolof 1,2-c1oxazol-5 (3H) -one (C160). A solution of compound C154 (1.01 g, 5.0 mmol) in THF (25 ml) was slowly treated with LDA (2 M, 3.8 ml) at 78 ° C. After 30 min at -78 ° C, a previously cooled solution (-78 ° C) of NFSI (2.58 g, 8.0 mmol) in THF (25 ml) was added by a cannula. After 20 min, the reaction was activated with water (4 ml) at -78 ° C and heated to 25 ° C. The solution was diluted with additional water (25 ml) and extracted with MTBE (25 ml). The aqueous phase was extracted 3 times with MTBE (20 ml each), and the combined MTBE extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by

184 chromatography to obtain the title compound C160. Yield: 350 mg (32%).¹H NMR (400 MHz, CDCI₃) δ 5.29 (dd, 1 H), 4.48 - 4.66 (m, 1 H), 4.51 (ddd, 1 H),

4.11 (dt, 1 H), 3.99 - 4.06 (m, 1 H), 3.71 - 3.79 (m, 1 H), 2.98 - 3.08 (m, 1 H), 1.75 2.07 (m, 2 H), 1.68 (s , 3 H), 1.49 (s, 3 H). ¹⁹F NMR (376 MHz, CDCI3) δ -198.87, 219.80. Also obtained (6R, 7S, 7aS) -6-fluoro-7- (2-fluoroethyl) -3,3-dimethyltetrahydropylIo- [1,2-c] oxazol-5 (3H) -one (C161). Yield: 516 mg (47%).¹H NMR (400 MHz, CDCI3) δ 4.83 (dd, 1 H), 4.58-464 (m, 1 H), 4.44-4.53 (m, 2 H),

3.99 (dd, 1 H), 3.57 (dd, 1 H), 2.64 - 2.79 (m, 1 H), 1.72 - 2.01 (m, 2 H), 1.65 (s, 3 H), 1.51 (s, 3 H ). ¹⁹F NMR (376 MHz, CDCI₃) δ -185.95, -219.45.

Stage 2, Epimerization of (6R, 7S, 7aS) -6-fluoro-7- (2-fiuoroethyl) -3,3-dimethyltetrah, dropyrol-f1,2-c] oxazol-5 (3H) -one (C161) . LDA (2 M, 0.34 ml) was added to a solution of compound C161 (100 mg, 0.46 mmol) in toluene (2 ml) at about -78 ° C. The mixture was stirred for 30 min, after which a solution of BHT was added at about -78 ° C (201 mg, 0.91 mmol) in toluene (4 mL). Immediately after the addition of BHT, water (4 ml) was added, and the mixture was heated to about 20 ° C. MTBE was added, and the phases were separated. The MTBE extract was dried in MgSO₄, was filtered and concentrated. The residue was purified by chromatography to obtain compound C160. Yield: 36 mg (36%).

Step 3. Synthesis of (3S, 4S, 5S) -3-fluoro-4- (2-fluoroethyl) -5- (hydroxymethyl) pyrrolidine-2-one (L121), to a stirred solution of compound C160 (460 mg, 0.39 mmol) in 21 ml of acetonitrile and 5 ml of water, TFA (8 ul, 0.1 mmol) was added. The reaction mixture was heated at 90 ° C for 1 h. The reaction mixture was cooled to 25 ° C, concentrated, then re-dissolved twice in acetonitrile and water, and concentrated. The residue was triturated with CHCI₃ to obtain the title compound L121. Yield: 270 mg (72%).¹H NMR (400 MHz, CD3OD) δ 4.86 (dd, 1 H), 4.62 - 4.70 (m, 1 H), 4.50 - 4.58 (m, 1 H), 3.71 - 3.82 (m, 2 H), 3.50 - 3.57 (m, 1 H), 2.78 (m, 1 H), 1.95 - 2.10 (m, 2 H). ¹⁹F NMR (376 MHz, CD3OD) δ -194.88, -217.30.

Preparation 73: 3- (hydroxomethyl) -4- (trifluoromethyl) pyrrolidine-1-carboxylate of (±) - (3R, 4R) tert-butyl (L122)

-185-

<img file="CU20160149A7_D0131.tif" />

Step 1. Synthesis of 1-benzyl-4- (trifluoromethyl) pyrrolidin-3-carboxylate (±) - (3R, 4R) ethyl (C164). To a solution of (E) -4,4,4-ethyl trifluorocrotonate (CAS 25597-16-4, 6.0 g, 36 mmol) and TFA (0.55 ml, 7 mmol) in DCM (60 ml) at about 0 ° C, N- (methoxymethyl) -N - [(trimethylsilyl) methyl] -benzemethanamine (CAS 93102-05-7, 16.85 g, 71 mmol) was added over a period of about 20 minutes. The reaction mixture was then heated at reflux for 16 h. It was diluted with DCM (100 ml), washed with saturated aqueous NaHCO solution₃ (2 x 100 ml), water (100 ml) and brine (50 ml). The DCM extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C164. Yield: 10.5 g (99%).¹H NMR (400 MHz, dmso-d₆) δ 7.23 - 7.34 (m, 5 H), 4.07 4.15 (m, 2 H), 3.64 (d, 1 H), 3.54 (d, 1 H), 3.35 - 3.41 (m, 1 H), 3.12 (q , 1 H), 2.81 (t, 2 H), 2.69 - 2.73 (m, 1 H), 2.55 - 2.59 (m, 1 H), 1.17 (t, 3 H).

Step 2. Synthesis of (±) - (3R, 4R) -1-tert-butyl 3-ethyl 4- (trifluoromethyl) pyrrolidine-1,3-dicarboxylate (C165). To a solution of compound C164 (2.0 g, 6.6 mmol) and dit-t-butyl dicarbonate (2.3 ml, 9.97 mmol) in EtOH (30 ml), palladium hydroxide on carbon was added (600 mg), and the mixture was stirred under a hydrogen atmosphere (1 atm) for about 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography to provide the title compound C165. Yield: 1.8 g (87%).¹H NMR (400 MHz, dmso-d6) δ 4.13 (q, 2 H), 3.60 3.68 (m, 2 H), 3.43 - 3.59 (m, 2 H), 3.25 - 3.39 (m, 2 H), 1.39 ( s, 9 H), 1.19 (t, 1 H). Step 3. Synthesis of 3- (hydroxymethyl) -4- (trifluoromethyl) pyrrolidine-1-carboxylate of (±) (3R, 4R) -ter-butyl (L122). A solution of compound C165 (1.8 g, 5.8 mmol) in THF (20 ml) was cooled to about 0 ° C, and lithium borohydride (630 mg, 29 mmol) was added portionwise. The mixture was heated at reflux for about 16 hours. It was then cooled to about 25 ° C and diluted with EtOAc (50 ml). The EtOAc extract was washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography to obtain the title compound L122. Yield: 1.3 g (83%).¹H NMR (400 MHz, dmso-d6) δ 4.95 (t, 1 H), 3.55 (br. S, 1

-186Η), 3.33 - 3.46 (m, 4 Η), 3.14 - 3.19 (m, 1 Η), 3.02 (br. S, 1 Η), 2.44 (br. S, 1 H), 1.39 (s, 9H) .

Preparation 74: (3S, 4S, 5S) -3,4-d? -4-et¡l-3-fluoro-5- (h¡drox¡met¡l) p¡rrol¡d¡n-2-one (L123)

<img file="CU20160149A7_D0132.tif" />

Step 1. Synthesis of (S) -7-ethyl-6-fluoro-3,3-dimethyl-1,7a-dihydropyrrolo | 1,2-cjoxazol5 (3H) -one (C172). A solution of compound C62 (2.00 g, 9.9 mmol) and diphenyl disselenide (3.32 g, 10.4 mmol) in THF (40 mL) was treated with lithium hexamethyldisilazide (1 M, 10.4 mi) at about 0 ° C. The mixture was kept at about 0 ° C for about 30 min, then heated at about 25 ° C for about 3 h. Water and EtOAc were added, and the phases separated. The aqueous phase was extracted with EtOAc, and the combined EtOAc extracts were dried over Na₂SW₄, filtered and concentrated. The residue was dissolved in DCM (100 mL) and pyridine (5.1 mL, 63 mmol) and treated with hydrogen peroxide (30%, 4.8 mL, 47 mmol) at about 0 ° C. The mixture was stirred at about 0 ° C for about 30 min, then heated at about 25 ° C for about 2 h. The mixture was washed with NaHCO₃ saturated aqueous, 1 M NaOH (twice), water and brine. The DCM extract was dried in MgSO₄, was filtered and concentrated. The residue was purified by chromatography to obtain the title compound C172. Yield: 1.56 g (55%).¹H NMR (400 MHz, CDCb) δ 4.36 (dt, 1 H), 4.21 (dd, 1 H), 3.27 - 3.37 (m, 1 H), 2.31 - 2.50 (m, 2 H), 1.67 (s, 3H ), 1.57 (s, 3H), 1.16 (t, 3 H).

Stage 2. Synthesis of (3S, 4S, 5S) -3,4-d_?-4-et¡l-3-fluoro-5- (hydroxymethyl) prolrolid-2-one (L123). A solution of compound C172 (1.20 g, 6.0 mmol) in ethanol-di (50 mL) was treated with a roller-on-carbon catalyst (5 mg) and stirred under a deuterium atmosphere at a pressure of 1 atmosphere and at a temperature of about 20 ° C for about 2 h. The mixture was filtered and concentrated. The residue was purified by chromatography to obtain the title compound L123. Performance; 250 mg (25%).¹H NMR (400 MHz, CDCI₃) δ 7.02 (br. s „1 H), 3.72 - 3.82 (m, 2 H), 3.55 3.66 (m, 1 H), 2.61 (t, 1 H), 1.59-1.71 (m, 1 H), 1.44 - 1.57 (m, 1 H), 1.06 (t, 3 H).

-187 Preparation 75: (3R, 4R, 5S) -3-fluoro-4- (fluoromethyl) -5- (hydroxymethyl) prolrold-2-one

U24)

Stage 1. Synthesis of (3R, 4R, 5S) -3-fluoro-4- (fluoromethyl) -5- (hydroxymethyl) pyrrolidine-2-one (1-124). To a stirred solution of compound C159 (70 mg, 0.34 mmol) in 4 ml of acetonitrile and 1 ml of water, TFA (3 ul, 0.03 mmol) was added. The reaction mixture was heated at 90 ° C for 1 h. The reaction mixture was cooled to 25 ° C and concentrated to obtain the title compound L124. Yield: 69 mg (100%).¹H NMR (400 MHz, CD₃OD) δ 5.07 (dd, 1 H) 4.89 - 4.80 (m, 3 H), 4.79 - 4.67 (m, 1 H), 3.76 (td, 1 H),

3.67 - 3.58 (m, 2 H), 3.13 - 2.92 (m, 1 H). ¹⁹F NMR (400 MHz, CD₃OD) δ -193.07, 226.18.

Preparation 76: 4- (hydroxymethyl) -5-azasp¡rof2.41heptan-6-one (L125)

<img file="CU20160149A7_D0133.tif" />

Stage 1. Synthesis of ethyl 2-cyclopropyl ethyl acetate (C180). To a stirred solution of 1-ethoxy-1 - [(trimethylsilyl) oxy] -cyclopropane (CAS 27374-25-0, 10 g, 57 mmol) in toluene (50 ml), (carbetoxymethylene) triphenylphosphorane (CAS 1099-) was added 45-2, 26 g, 74 mmol) and then benzoic acid (0.91 g, 7.5 mmol) at about 25 ° C. The mixture was heated overnight at about 90 ° C, then cooled and concentrated. The residue was purified by chromatography to obtain the title compound C180. Yield: 3.2 g (44%).¹H NMR (400 MHz, CDCI₃) δ 6.22 (s, 1 H), 4.14 (q, 2 H),

1.40-1.46 (m, 2 H), 1.27 (t, 3 H), 1.20-1.24 (m, 2 H).

Step 2. Synthesis of 2- (1- (tromethyl) cyclopropyl) ethyl acetate (C181). A solution of compound C180 (2.3 g, 18 mmol), nitromethane (4.90 mL, 91 mmol) and DBU (2.73 mL, 18 mmol) in MeCN (50 mL) was heated overnight at about 60 ° C The mixture was cooled, diluted with EtOAc and washed with saturated aqueous NH4CI solution. The EtOAc was separated, and the aqueous phase was extracted with EtOAc. The combined EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue was purified by chromatography to obtain the title compound C181. Yield: 1.7 g (50%).¹H NMR (400 MHz, CDCI₃) δ 4.41 (s, 2 H), 4.15 (q, 2 H),

2.48 (s, 2 H), 1.26 (t, 3 H), 0.80 - 0.83 (m, 2 H), 0.70 - 0.74 (m, 2 H).

-188 Stage 3. Synthesis of 2- (1- (2-hydroxy-1-nitroethyl) cyclopropyl) ethyl acetate (C182). A solution of compound C181 (2.5 g, 13 mmol), paraformaldehyde (0.802 g, 26 mmol) and potassium fluoride (78 mg, 1.3 mmol) in 2-propanol (30 mL) was stirred for about 36 has about 25 ° C, and then concentrated. The residue was purified by chromatography to obtain the title compound C182. Yield 1.1 g (38%).¹H NMR (400 MHz, CDCI₃) δ 4.14 (q, 2 H), 4.03-4.10 (m, 2 H), 3.92-3.96 (m, 1 H),

3.16 - 3.20 (m, 1 H), 2.86 (d, 1 H), 2.23 (d, 1 H), 1.27 (t, 3 H), 0.90 - 0.99 (m, 2 H), 0.79 - 0.83 (m, 1 H), 0.64 - 0.68 (m, 1 H).

Step 4. Synthesis of 4- (hydroxymethyl) -5-azaspirof2.41heptan-6-one (L125) To a solution of compound C182 (600 mg, 2.7 mmol) in EtOH (10 ml) was added platinum dioxide ( 60 mg), and the mixture was stirred under a hydrogen atmosphere (1 atm) for about 20 h at about 25 ° C. The mixture was filtered, and the filtrate was heated at about 80 ° C for about 24 h, then concentrated. The residue was purified by chromatography to obtain the title compound L125. Yield: 220 mg (56%). ¹H NMR (400 MHz, dmso-d₆) δ 7.70 (br. s., 1 H), 4.66 (t, 1 H), 3.25 - 3.39 (m, 2 H), 3.08 (t, 1 H), 2.39 (d, 1 H), 1.89 (d , 1 H), 0.73-0.86 (m, 1 H), 0.40-0.61 (m, 3 H).

Preparation 76: 1- (j (2R, 3R, 4S) -3-ethyl-4-fluoro-3-hydrox¡-5-oxop¡rrolidin-2-ljmetox¡} -7methoxysoquinolin-6-carboxamide

<img file="CU20160149A7_D0134.tif" />

Step 1. Sterile medium was prepared using deionized water containing dextrose (10 g / l), glycerol (20 g / l), yeast extract Different (5 g / l), Nutrisoy flour (5 g / l), NaCl ( 5 g / l), K₂HPO₄ (5 g / l), P2000 (1 ml / l), pH adjusted to 7.0 before autoclaving to sterilize.

Stage 2. Streptomyces spectabilis ATCC 27465 was cultured in 25 ml of this medium which had been added to each of the three sterile Nalgene flasks (250 ml, with

-189 decreased pressure, vented closures) on a 2 ”swivel swing shaker at 30 ° C, 210 rpm, for two days. The content of each flask was aseptically transferred to each of the 2 I Nalgene sterile flasks (with reduced pressure, vented closures) containing 400 ml of the same sterile medium, then incubated as indicated above. After two days, 16 ml of a solution of 1 - {[(2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxoprolroldin-2-yl] methoxy, -7-methoxyisoquinolin was added -6-carboxamide in DMSO (5 mg / ml) to each flask. Incubation continued as indicated above; Samples were taken aseptically from the flasks every 24 hours. After three days, the flask content was combined and extracted twice with an equal volume of ethyl acetate. The organic phases were combined, dried with anhydrous sodium sulfate, then concentrated in vacuo to obtain 3.7 g of brown oil.

Step 3. High resolution preparative liquid chromatography was used using 0.1% trifluoroacetic acid in water with acetonitrile gradient on a Phenomenex Luna phenyl-hexyl column to isolate compounds from the previous preparation. Time-based fraction collection was used to collect all peaks of interest. Each sample was dried and evaluated by LCMS to confirm the identification of retention time and the origin ion of m / z = 378 daitons. 1 {[(2R, 3R, 4S) -3-etiI-4-fluoro-3-hydroxy-5-oxopirroIidin-2-I] methoxy} -7-methoxyisoquinolin-6carboxamide (Example 196): ¹H NMR (600 MHz, dmso-d₆) δ 8.85 (s, 1H), 8.17 (s, 1H),

7.91 (d, 1H), 7.85 (br. S, 1H), 7.71 (s, 2H), 7.45 (d, 1H), 4.58 (dd, 1H), 4.48 (d, 1H),

4.30 (dd, 1H), 3.98 (s, 3H), 3.87 (dd, 1H), 1.72 (q, 2H), 1.01 (t, 3H).

The following two examples were also prepared:

1 - {[(3S, 4S) -3-ethyl-4-fluoro-2-hydroxy-5-oxopyrrolidin-2-yl] methoxy} -7methoxyisoquinolin-6-carboxamide (Example 197), as a mixture of diastereomers: Diastereomer primary; ¹H NMR (600 MHz, dmso-d₆) δ 9.25 (s, 1H), 8.18 (s, 1H), 7.92 (d, 1H), 7.6 (s, 1H), 7.72 (s, 1H), 7.6 (s, 1H), 7.54 (s, 1H) , 4.96 (dd, 1H), 4.5 (dd, 2H),

3.98 (s, 3H), 2.47 (m, 1H), 1.67 (m, 1H), 0.99 (t, 3H). Secondary diastereomer¹H NMR (600 MHz, dmso-d₆) δ 9.18 (s, 1H), 8.16 (s, 1H), 7.91 (d, 1H), 7.83 (s, 1H), 7.71 (s, 1H), 7.69 (s, 1H), 7.44 (s, 1H) , 5.14 (dd, 1H), 4.5 (dd, 2H), 3.92 (s, 3H), 2.39 (m, 1H), 1.58 (m, 1H), 0.99 (t, 3H).

-190

1 - {[(2S, 3R, 4S) -4-fluoro-3- (1-hydroxyethyl) -5-oxopyrrolidin-2-yl] methox!} -7methoxyssoquinolin-6-carboxamide (Example 198): ¹H NMR (600 MHz, dmso-d₆) δ 9.0 (s, 1H), 8.17 (s, 1H), 7.91 (d, J 1H), 7.86 (br s, 1H), 7.76 (s, 1H), 7.71 (bs, 1H), 7.44 (d, 1H), 4.94 (d, 1H), 4.83 (dd, 1H), 4.60 (dd, 1H), 4.26 (dd, 1H), 4.07 (m, 1H), 3.99 (m, 1H), 3.916 (m, 1H ), 2.56 (m, 1H), 1.23 (d, 3H).

METHODS

The methods indicated below are only intended to exemplify different aspects and embodiments of the invention, and are not intended to limit the scope of the claimed invention in any way. It will be apparent to a person of the mid-level trade that the methods described below can be modified in different ways, for example, by changing reaction solvents or volumes, substituting reagents similar to those described, or substituting catalysts similar to those described.

Method 1

<img file="CU20160149A7_D0135.tif" />

A reactant B, such as tert-butyl 4- (hydroxymethyl) pperidin-1-carboxylate (CAS 123855-51-6, commercially available, 28 mg, 0.13 mmol) was dissolved in 0.5 ml of DMSO, and a reactant A, such as 1-chloro-7-isopropoxyisoquinolin-6carbonitrile (P2) (0.2 M in DMSO, 0.5 ml, 0.10 mmol) was added. The mixture was then treated with potassium tert-butoxide (1 M in THF, 0.13 mL, 0.13 mmol). The reaction mixture was heated at about 50 ° C to about 100 ° C for about 2 to 16 hours until the reaction was determined to be complete. The mixture was then cooled to about 25 ° C and filtered, and the filtrate was concentrated. The residue can be used

-191 directly in the next step, or it can be purified by chromatography or HPLC.

<img file="CU20160149A7_D0136.tif" />

To a solution of a B reactant, such as (3S, 5S) -3-fluoro-5- (hydroxymethyl) -3-methyl-pyrrolidin-2-one (L10) (314 mg, 2.1 mmol) in 15 ml of DMF , sodium hydride (60% in mineral oil, 342 mg, 8.6 mmol) was added at about 25 ° C, and the mixture was stirred for about 15 minutes. A reactant A, such as 1-chloro-7methoxyisoquinolin-6-carbonitrile (P1) (513 mg, 2.3 mmol) was added, and stirring continued for about 16 h. The reaction was quenched with EtOAc and water at about 0 ° C. The mixture was extracted with EtOAc, and the EtOAc separated, washed with brine, dried over Na₂SW₄, was filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 3

<img file="CU20160149A7_D0137.tif" />

A reactant B, such as (3R, 4S, 5S) -5- (hydroxymethyl) -3-methoxy-4-methylpyrrolidin-2-one (L65) (105 mg, 0.66 mmol), and a reactant A, such as 1 -chloro-7methoxyisoquinol-6-carbonitrlo (P1) (120 mg, 0.55 mmol), stirred in DMF (15 ml) at about 25 ° C. A solution of potassium hexamethyldisilazide (1 M in THF,

-1921.37 ml) was added dropwise to the reaction mixture. After the addition of potassium hexamethyldisilazide was completed, the reaction was stirred for approximately 50 more minutes. The reaction mixture was then poured into a mixture of saturated aqueous NH solution.₄CI and EtOAc with vigorous stirring. The EtOAc was separated, washed with water, brine, dried over Na₂SW₄, was filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

<img file="CU20160149A7_D0138.tif" />

Method 4

<img file="CU20160149A7_D0139.tif" />

A reactant B, such as tert-butyl 4-hydroxypiperin-1-carboxylate (CAS 109384-19-2, commercially available, 50 mg, 0.2 mmol), a reactant A, such as 4-chloro -6-isopropoxy-quinolin-7-carboxamide (P4) (30 mg, 0.1 mmol), and cesium carbonate (300 mg, 0.9 mmol) were combined in a small microwave container and diluted with 1 ml of DMSO. The vessel was capped and heated in a microwave reactor at about 150 ° C for about 15 minutes. The reaction mixture was then diluted with EtOAc and water, and the phases were separated. The aqueous phase was extracted three times with EtOAc, and the combined EtOAc extracts were dried and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC. In some cases, potassium carbonate can be used instead of cesium carbonate.

Method 5

-193o,

<img file="CU20160149A7_D0140.tif" />

Triphenylphosphine (1.59 g, 5.9 mmol) was added to a suspension of a B reactant, such as (4R, 5S) -5- (hydroxymethyl) -4-methylpyrrolidin-2-one (L36) (393 mg, 2 mmol) and a reactant A, such as 5-hydroxy-3-methoxy-2-naphthamide (P5) (430 mg, 2 mmol) in 10 ml of THF. Diisopropyl azodicarboxylate (0.84 g, 3.9 mmol) was added dropwise. The mixture was stirred at about 20 ° C for 6 days and then concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

<img file="CU20160149A7_D0141.tif" />

A solution of a B reactant, such as (5S) -5- (hydroxymethyl) -3methoxypyrrolidin-2-one (L25) (264 mg, 2 mmol) in 15 ml of DCM was treated with p-toluenesulfonyl chloride (760 mg , 4 mmol) and DMAP (512 mg, 4 mmol). The reaction mixture was stirred for about 12 h at about 25 ° C. The mixture was washed with water (15 ml). The DCM dried up in Na₂SW₄, was filtered and concentrated. The residue was purified by silica gel chromatography to obtain 312 mg (52%) of the L25 p-toiuenesulfonate ester intermediate.

To a solution of the L25 p-toluenesulfonate ester intermediate prepared above (166 mg, 0.55 mmol) in dry DMF (5 mL), cesium carbonate (357 mg, 1.1 mmol) and a reactant A were added, such as 5-hydrox-3-methoxy-2-naphthamide (P5) (132 mg, 0.6 mmol). The mixture was stirred for about 2 h at about 65 ° C. -194 The DMF was evaporated, the residue was stirred with EtOAc, and the mixture was filtered. The filter cake was washed with water (5 ml x 2). The filter cake was dried under vacuum, treated with EtOAc and filtered. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 7

<img file="CU20160149A7_D0142.tif" />

A solution of a reactant, such as 4 - (((6-Cano-7-sopropox, soquinolin-1-yl) ox), methyl) -piperidine-1-tert-butyl carboxylate (42 mg, 0, 10 mmol) in DMSO (1 mL) was treated with K₂CO₃ powder (41 mg, 0.30 mmol) and then with 30% hydrogen peroxide solution (0.2 ml, 1.8 mmol). The mixture was heated at about 40 ° C to 60 ° C for about 15 minutes to 16 hours until the reaction was determined to be complete. The mixture was then cooled to about 25 ° C and filtered, and the filtrate was concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC. In some cases, sodium hydroxide or potassium hydroxide can be replaced by K₂CO₃.

Method 8

<img file="CU20160149A7_D0143.tif" />

-195 A solution of a reactant, such as 1 - ((((2S, 3S, 4S) -3-ethyl-4-fluoro-5oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinone-6-carbonitrile ( 200 mg, 0.5 mmol) in H₂SW₄ concentrate (1.5 ml) was heated at about 55 ° C for about two hours, then cooled to about 20 ° C. The reaction mixture was added dropwise with vigorous stirring to 7.3 ml of ice cold concentrated ammonium hydroxide with ice cooling. The precipitated solid was filtered and washed with water, heptane, ether, and dried in vacuo. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 9

<img file="CU20160149A7_D0144.tif" />

A solution of a reactant, such as 1 - (((2S, 4R) -4 - ((benzyloxy) methyl) -4-fluoro5-oxopyrrolidin-2-yl) methoxy) -7-sopropoxyisoquinol-6 -carboxamide (20 mg, 0.44 mmol) in MeOH (0.46 ml) was treated with a palladium on carbon catalyst (5 mg) and stirred under a hydrogen atmosphere at a pressure of about 1 to 5 atmospheres and a temperature of about 20 ° C to 65 ° C. The mixture was then cooled to about 20 ° C and filtered, and the filtrate was concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 10

-196-

<img file="CU20160149A7_D0145.tif" />

Ck .0

<img file="CU20160149A7_D0146.tif" />

reactant, such as tert-butyl 4 - (((6-carbamoyl-7-sopropoxyisoquinolin-1-yl) oxy) methyl) piperidine-1-carboxylate (44 mg, 0.1 mmol) at 1.0 a 2.0 ml of a suitable solvent, such as DCM, was treated with TFA (0.10 ml) or hydrogen chloride (4 M in dioxane, 0.4 ml). The reaction mixture was heated at about 30 ° C to 40 ° C for about 1 to 4 hours until the reaction was determined to be complete. The mixture was then cooled to about 25 ° C, concentrated in vacuo and purified by chromatography or HPLC.

Method 11

<img file="CU20160149A7_D0147.tif" />

CN

A solution of a reactant, such as 7-isopropoxy-1- (pperidin-4-methoxy), soquinolin-6-carboxamide (41 mg, 0.12 mmol) in DMF (1.0 ml) was treated with acid cyanoacetic acid (11 mg, 0.12 mmol), and then with HATU (47 mg, 0.12 mmol) and Et₃N (35 pl, 0.25 mmol). The reaction mixture was heated at about 30 ° C to 50 ° C for about 4 to 16 hours until the reaction was determined to be complete. The mixture was then cooled to about 25 ° C, concentrated in vacuo and purified by chromatography or HPLC.

-197 Method 12

<img file="CU20160149A7_D0148.tif" />

A solution of a reactant, such as 1 - (((2S, 3S, 4S) -3-ethyl-4-fluoro-5oxopyrrolidin-2-yl) methoxy) -7-methoxyisoquinolin-6-carboxamide (500 mg, 1, 4 mmol) in DMF (15 ml) was treated with SelectFIuor® (511 mg, 1.4 mmol), and heated at about 55 ° C for about 24 h. The mixture was concentrated, xylene was added, and the mixture was concentrated again. The concentration with xylene was repeated two more times, and the residue was stirred with EtOAc. The precipitated solid was filtered and washed with EtOAc, and the EtOAc filtrates were combined, concentrated and treated with EtOAc and water. The EtOAc was separated, concentrated in vacuo and purified by chromatography or HPLC.

<img file="CU20160149A7_D0149.tif" />

A solution of a reactant, such as (S) -methyl 3-methoxy-5 - ((5-oxopyrrolidin-2-yl) methoxy-2-naphthoate (366 mg, 1.1 mmol) in THF (25 mL) and water (25 ml) was treated with lithium hydroxide (272 mg, 11.1 mmol) The resulting mixture was stirred at about 25 ° C for about 1 hour, then the mixture was partially concentrated in vacuo to remove THF. The remaining solution was acidified with 10% aqueous citric acid, and the resulting precipitate was collected by filtration, washed with water and dried. -198 The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

<img file="CU20160149A7_D0150.tif" />

A solution of a reactant, such as (S) -methyl 3-methoxy-5 - ((5-oxopyrrolidin-2-yl) methoxy) 2-naphthoate (385 mg, 1.2 mmol) in THF (25 ml) was treated with Et₃N (0.26 ml,

1.8 mmol) and heated to reflux. The mixture was cooled to about 25 ° C, then BOP reagent (CAS 56602-33-6, 709 mg, 1.6 mmol) was added. The mixture was stirred for about 25 min, until most of the BOP reagent dissolved, then ammonium hydroxide (15 M, 1.5 ml) was added. After about 45 min, the mixture was filtered, and the filtrate was concentrated. The residue was treated with water, and the resulting precipitate was collected by filtration, washed with water and dried. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 15

<img file="CU20160149A7_D0151.tif" />

A solution of a reactant, such as (S) -7-isopropoxy-1 - ((5-oxopyrrolidin-2-yl) methoxy) -isoquinolin-6-carbonitrile (100 mg, 0.3 mmol) in acetonitrile (6.1 ml ) [omission in the source text] with N-bromosuccinimide (55 mg, 0.3 mmol), heated at about 60 ° C for about 1.5 h. An additional portion of N-199bromosuccinimide (30 mg 0.14 mmol) was added. After about 30 min, the mixture was cooled to about 25 ° C and diluted with 10 ml of EtOAc. The EtOAc extract was washed with saturated aqueous sodium thiosulfate (10 ml). The aqueous phase was reextracted with EtOAc (10 mL), and the combined EtOAc extracts were washed with saturated aqueous sodium thiosulfate (15 mL), brine (15 mL), dried over Na₂SW₄₎They were filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 16

<img file="CU20160149A7_D0152.tif" />

A solution of a reactant, such as (S) -4-bromo-7-lsopropoxy-1 - ((5oxoprolroldin-2-l) methox), soquinolin-6-carbontrol (54 mg, 0.1 mmol), bls (triphenylphosphine) palladium chloride (19 mg, 0.03 mmol), potassium methyltrifluoroborate (25 mg, 0.2 mmol) and K₂CO₃ (55 mg, 0.4 mmol) in acetonltrllo (0.75 ml) and water (0.5 ml) was heated in a microwave reactor at about 125 ° C for about 30 min. The mixture was diluted with EtOAc (10 mL) and washed with brine. The aqueous phase was reextracted with EtOAc (10 mL), and the combined EtOAc extracts were dried over Na₂SW₄, filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 17

-200-

<img file="CU20160149A7_D0153.tif" />

<img file="CU20160149A7_D0154.tif" />

A solution of a reactant, such as 7-¡-sopropoxy-1 - (((3aS, 6R, 6aR) -1methoxy-2-oxooctahydroc¡clopenta [b] pyrrol-6-¡l) ox¡) soquinolin-6- Carboxamide (42 mg, 0.1 mmol) in 3.25 ml of acetonitrile and 0.25 ml of water was treated with molybdenum hexacarbonyl (34 mg, 0.13 mmol). The reaction was heated at reflux for about 18 h. The mixture was cooled to about 25 ° C, diluted with MeOH, filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 18

<img file="CU20160149A7_D0155.tif" />

A solution of a reactant, such as (±) -1 - ((1 R, 6S) -3azab¡c¡clo [4.1.0] heptan-1-ylmethoxy) -7-sopropoxyisoquinolin-6-carboxamide ( 54 mg, 0.15 mmol) and di-t-butyl dicarbonate (37 mg, 0.17 mmol) in THF (2 ml) and water (2 ml) was stirred for about 45 min at about 25 ° C , then diluted with EtOAc and water. The EtOAc was separated, washed with brine, dried over Na₂SW₄, was filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

-201 Method 19

<img file="CU20160149A7_D0156.tif" />

A solution of a reactant, such as (S) -7-isopropox¡-1 - ((5-oxopyrrolidin-2-yl) methoxy) -isoquinolin-6-carboxamide (272 mg, 0.80 mmol) in 1.4 -dioxane (20 ml) was treated with 5 ml of H₂SW₄ 50% cold The mixture was heated at about 55 ° C for about 24 h, then cooled to about 25 ° C and allowed to stand for about 18 h. The dioxane was separated, and the aqueous phase was neutralized at about pH 5 with K₂CO₃, then extracted repeatedly with EtOAc. The combined dioxane and EtOAc extracts were dried in Na₂SW₄, filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 20

<img file="CU20160149A7_D0157.tif" />

A solution of such as (S) -5 - (((6-bromo-7a reactant, such (trifluoromethoxy), soquinolin-1-yl) oxy) methyl) pyrrolidin-2-one (78 mg, 0 , 19 mmol) and zinc cyanide (46 mg, 0.38 mmol) in DMF (2.5 ml) was treated with tetrakis (triphephosphine) palladium (0) (45 mg, 0.04 mmol). The mixture was heated for about 20 min at about 150 ° C, then diluted with ice water (35 ml) and filtered. The precipitate was dissolved in DCM, washed with brine, dried over Na₂SW₄, was filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

-202 Method 21

<img file="CU20160149A7_D0158.tif" />

A solution of a reactant, such as 1 - (((1S, 3aS, 6aR) -5-benzyl-3-oxoctahydropyrrolo [3,4-c] pyrrol-1-yl) methoxy) -7-sopropoxyisoquinolin-6-carboxamide ( 50 mg, 0.10 mmol), aqueous formaldehyde solution (37%, 6 ml) in MeOH (50 ml) were treated with a palladium on carbon catalyst (5 mg) and stirred under a hydrogen atmosphere at a pressure of 1 atmosphere and a temperature of around 20 ° C for about 2 h. The mixture was filtered and concentrated. The residue can be used directly in the next step, or it can be purified by chromatography or HPLC.

Method 22

<img file="CU20160149A7_D0159.tif" />

A solution of a reactant, such as (S) -4-bromo-7-isopropox¡-1 - ((5oxopyrrolidin-2-yl) methoxy) isoquinolin-6-carbontril (1.0 g, 2, 4 mmol) in 1,4-dioxane (20 mL) was treated with freshly dried potassium acetate (729 mg, 7.4 mmol), bis (diboro pinacolato) (880 mg, 3.5 mmol), and tetrakis (triphenylphosphine) ) paiadium (0) (143 mg, 0.12 mmol). The mixture was heated at about 100 ° C for about 16 h. The mixture was cooled to about 25 ° C, filtered and concentrated. The residue can be

-203use directly in the next step, or it can be purified by chromatography or HPLC.

EXAMPLES

1-ff (2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxopyrrolidin-2-immethoxy) -7methoxysoquinolin-6-carboxamide

Step 1. Synthesis of (7R, 7aS) -7-ethyl-3,3-dimethyltetrahydropyrrolo [1,2-C1 -xazol-5 (3H) -one (C54).

A suspension of copper bromide and dimethyl sulfide complex (833 g, 4.05 mol) in diethyl ether (6 I) was cooled to about -20 to -30 ° C, and a solution of ethylmagnesium bromide ( 2M in THF, 4.05 I, 8 moles) for about 1 hour, which allowed the temperature to rise to about -3 ° C. After stirring for about 10 min, the suspension was cooled to about -70 ° C, and TMSCI (382 ml, 3.04 mol) was added dropwise for about 1 h. After about 50 min, P20 compound (310 g, 2.02 mol) in 500 ml of MTBE was added dropwise to the mixture for about 2 hours. The temperature was maintained at about -72 to -68 ° C during the addition. The reaction mixture was stirred at about -72 ° C for about 4 hours, after which it was heated at about -40 ° C for about 16 hours. The reaction mixture was quenched with NH₄Semisaturated aqueous IC (4 I). After phase separation, the solvent phase was washed with water, dried over Na₂SW₄, was filtered and concentrated. The reaction was performed six times in total, and the combined crude products were purified by silica chromatography to obtain the title compound C54. Yield 1.4 kg (63%, based on 12.1 mol of P20).¹H NMR (400 MHz, CDCI₃) δ 4.34 (dt, 1 H),

3.90 (dd, 1 H), 3.72 (dd, 1 H), 2.91 (dd, 1 H), 2.31 (dd, 1 H), 2.25 (m, 1 H), 1.65 (s, 3 H), 1.52 ( d, 1 H), 1.48 (s, 3 H), 1.27 - 1.38 (m, 1 H), 0.92 (t, 3 H).

Step 2. Synthesis of (6S, 7S, 7aS) -7-ethyl-6-fluoro-3,3-dimethyltetrahydropyrrolo [1,2-cxaxazol-5 (3H) -one (C61)

A solution of diisopropylamine (184 ml, 1.31 mol) in THF (1.65 I) was cooled to about -20 to -30 ° C and treated with n-butyllithium solution (2.5 M in hexanes , 491 ml, 1.23 mol) for about 10 minutes, and the temperature was increased to

-204 around -20 ° C. After stirring for about 10 minutes, the solution was cooled to about -70 ° C, and a solution of compound C54 (235 g, 1.17 mol) in THF (588 ml) was added dropwise over about 30 minutes The temperature was maintained at about -70 to -60 ° C during the addition, and after stirring for about 30 minutes at this temperature, a solution of NFSI (387 g, 1.23 mol) in 1.2 was added I of THF for about 80 minutes at around -70 to -72 ° C. After stirring for about 1 h at about -70 to -60 ° C, the reaction was heated to about 20 ° C overnight. The precipitated solids were filtered and washed with THF (1 I). The filtrate was concentrated to an oily residue. This complete reaction was carried out three times on this scale and once using 500 g of compound C61. The combined crude products were purified by silica chromatography to obtain the title compound C61. Yield: 350 g (27% based on 6.6 mol of C54).¹H NMR (400 MHz, CDCI₃) δ 5.23 (dd, 1 H), 3.97 - 4.11 (m, 2 H), 3.68 - 3.77 (m, 1 H), 2.62 - 2.76 (m, 1 H), 1.69 - 1.79 (m, 1 H), 1.68 (s, 3 H), 1.45 - 1.52 (m, 3 H), 1.28 - 1.42 (m, 1 H), 0.97 (t, 3

H). ¹⁹F NMR (376 MHz, CDCI3) δ -199.61. Also obtained (6R, 7S, 7aS) -7-ethyl-6fluoro-3,3-dimethyltetrah ¡droprolo [1,2-c] oxazol-5 (3H) -one C62. Yield: 700 g (54% of 6.6 mol of C54).¹H NMR (400 MHz, CD3CN) δ 4.78 (dd, 1 H), 4.40 (dt, 1 H), 3.93 (dd, 1 H), 3.56 (dd, 1 H), 2.30 - 2.46 (m, 1 H), 1.56 (s, 3 H), 1.52 (ddd, 1 H), 1.42 (s, 3H), 1.35-1.48 (m, 1 H), 0.97 (t, 3 H). ¹⁹F NMR (376 MHz, CD₃CN) δ-185.41. Step 3. Epimerization of (6R, 7S, 7aS) -7-ethyl-6-fluoro-3,3-dimethyltetrah ¡drop¡rrolof1,2c] oxazol-5 (3H) -one (C62). To a solution of diisopropylamine (310 g, 3.07 mol) in toluene (4 I), n-butyllithium (2.5 M, 1.22 I, 3.05 mol) was added dropwise at -30 ° C . The mixture was kept at -30 ° C for an additional 30 min, then was added dropwise to a solution of compound C62 (556 g, 2.77 mol) in toluene (2 I) at -78 ° C for 2 h. After the addition was completed, the mixture was kept at -78 ° C for an additional 30 min before adding a solution of BHT (1.26 kg, 5.73 mol) in toluene (5)

I) for 3 h, keeping the Internal temperature below -65 ° C. After the addition was completed, the mixture was maintained at -78 ° C for 30 min. The mixture was heated to 25 ° C, water was added, and the toluene was separated. The aqueous layer was extracted with DCM twice, the combined toluene and DCM extracts dried over Na₂SO4, filtered and concentrated. The residue was purified by chromatography.

-205 to obtain compound C61. Performance; 250 g (45%). Compound C62 was also recovered. Yield: 150 g (27%).

Step 4. Synthesis of (3S, 4S, 5S) -4-ethyl-3-fluoro-5- (hydroxymethyl) pyrrolidine-2-one (L54).

HO

OR

HN

<img file="CU20160149A7_D0160.tif" />

A solution of compound C61 (90 g, 0.45 mol) in acetonitrile (450 ml) and water (45 ml) was treated with TFA (6.8 ml, 90 mmol). The mixture was heated at about 65 ° C for about 1 h and maintained at that temperature for about 3 h. The mixture was then cooled and about 350 ml of solvent was distilled off by rotary evaporation. The residue was diluted with acetonitrile (400 ml) and evaporated to dryness. Isopropyl acetate (250 ml) was added to the residue, and the mixture was concentrated again. The residue was diluted with heptane (200 ml), and crystallization was induced by seeding. The precipitate was filtered in two cultures to obtain the title compound L54. Yield: 46 g (64%).¹H NMR (400 MHz, CDCI₃) δ 7.59 (br. s., 1 H), 4.80 (dd, 1 H), 3.69 - 3.83 (m, 2 H), 3.52 - 3.64 (m, 1 H), 3.48 (br. s, 1 H) , 2.27 2.52 (m, 1 H), 1.57 - 1.73 (m, 1 H), 1.49 (dt, 1 H), 1.04 (t, 3 H). ¹⁹F NMR (376 MHz, CDCIs) δ-198.72.

Step 5. Synthesis of 1 - (((2S, 3S, 4S) -3-ethyl-4-fluoro-5-oxoprolroldin-2-yl) methoxy) -7-methoxyssoquinolin-6-carbonitrile (C171).

<img file="CU20160149A7_D0161.tif" />

A mixture of compound L54 (8.00 g, 49.6 mmol) and compound P1 (9.87 g, 45.1 mmol) was stirred in DMF (83 mL) and cooled to about -10 ° C. A solution of potassium hexamethyldisilazide (1 M in THF, 99 mL, 99 mmol) was added to the reaction mixture for about 45 minutes, keeping the internal reaction temperature at around -10 ° C. After the addition of potassium hexamethyldisilazide was completed, the reaction was stirred at about -10 ° C for -206 approximately 30 minutes more. A solution of 24.9 g of sodium diacid phosphate in 250 ml of water was prepared. The reaction mixture was then poured into 220 ml of this aqueous solution of sodium diacid phosphate and 250 ml of EtOAc with vigorous stirring. The reaction flask was rinsed with the remaining 30 ml of aqueous sodium diacid phosphate solution and the rinse was added to the EtOAc mixture. The EtOAc was separated. The aqueous mixture was extracted three times with EtOAc. The combined EtOAc extracts were dried over MgSO₄, filtered and concentrated. Xylene was added to the residue, and the mixture was concentrated. The addition of xylene and subsequent evaporation were performed twice more to obtain the title compound C171. Performance:

15.37 g (90%). ¹H NMR (400 MHz, dmso-d6) δ 8.89 (s, 1 H), 8.50 (s, 1 H), 7.98 (d, 1 Η), 7.80 (s, 1 H), 7.41 (d, 1 H) , 4.90 (dd, 1 Η), 4.56 (dd, 1 H), 4.24 (dd, 1 H), 4.09 (dt, 1 H), 4.03 (s, 3 H), 2.62 (m, 1 H), 1.58 (m, 2 H), 1.02 (t, 3 H). ¹⁹F NMR (376 MHz, dmsod6) δ-199.18.

Step 6. Synthesis of 1- {f (2S, 3S, 4S) -3-et¡l-4-fluoro-5-oxopyrrol¡d¡n-2-¡l'lmetox¡} -7methoxysoquinolin-6-carboxamide ( Example 296).

A mixture of compound C171 (15.37 g, 44.7 mmol) and methanesulfonic acid (218 ml, 3.36 mol) was heated at about 60 ° C with stirring for about 26 hours. The mixture was then cooled to about 25 ° C and slowly added to 1 kg of crushed ice with stirring. During the addition, an additional 150 g of ice was added, to ensure that, when the addition was finished, there was still ice in the mixture. Ethyl acetate (1 I) was added. Then, ammonium hydroxide (274 ml) was slowly added to the biphasic mixture under stirring, along with 750 g more of ice, until the pH of the mixture increased to about 8. The mixture was then heated to about 30 ° C to dissolve all solids present. The EtOAc was separated, and the aqueous phase was extracted with EtOAc (4 x 100 mL). The combined EtOAc extracts were washed with brine, dried over MgSO₄, filtered and concentrated to obtain the title compound. Yield 14.72 g (91%). Recrystallization of EtOH produced an analytically pure sample, mp 286 ° C.¹H NMR (400 MHz, dmsod₅) δ 8.86 (s, 1 H), 8.16 (s, 1 H), 7.90 (d, 1 H), 7.84 (br. s „1 H), 7.74 (s, 1 H), 7.69 (br. s„ 1 H), 7.43 (d, 1 H), 4.91 (dd, 1 H), 4.54 (dd, 1 H), 4.26 (dd, 1 H), 4.09 (br. S., 1 H),

3.97 (s, 3 H), 2.63 (m, 1 H), 1.60 (m, 2 H), 1.02 (t, 3 H). ¹⁹F NMR (decoupled H, 376 MHz, dmso-d₆) δ -199.26.

-207 The following compounds of the invention were similarly prepared using the methods described above. Reactants A were prepared as described herein. Reactants B were known compounds that were commercially available, or known compounds that were prepared as described in the cited references, or compounds prepared as described herein. For these examples characterized by the HPLC retention time, the following HPLC conditions were used^-.

<td>Method PF-AB01</td><td>PF-AB10 method</td><td>PF-CD05 method</td>

<td>Xbridge column C18 2.1 χ 50 mm 5pm</td><td>Xbridge column C18 2.1 χ 50 mm 5pm</td><td>Xbridge column C18 2.1 χ 50 mm 5gm</td>

<td>Temperature 50 ° C</td><td>Temperature 50 ° C</td><td>Temperature 50 ° C</td>

<td>Mobile phase A 0.0375% of TFA in water</td><td>Mobile phase A 0.0375% of TFA in water</td><td>0.05% NH mobile phase₄OH in water</td>

<td>Mobile phase B 0.01875% TFA in acetonitrile</td><td>Mobile phase B 0.01875% TFA in acetonitrile</td><td>100% acetonitrile B mobile phase</td>

<td>Gradient - Initial 1% of B</td><td>Gradient - Initial 10% of B</td><td>Gradient - initial 5% of B</td>

<td>Time 0.00 min 1% of B</td><td>Time 0.00 min 10% of B</td><td>Time 0.00 min 5% of B</td>

<td>Time 0.60 min 5% of B</td><td>Time 0.50 min 10% of B</td><td>Time 0.50 min 5% of B</td>

<td>Time 4.00 min 100% of B</td><td>Time 4.00 min 100% of B</td><td>Time 3.40 min 100% of B</td>

<td>Time 4.30 min 1% of B</td><td>Time 4.30 min 10% of B</td><td>Time 4.20 min 100% of B</td>

<td>Time 4.70 min 1% of B</td><td>Time 4.70 min 10% of B</td><td>Time 4.21 min 5% of B</td>

<td>Flow rate 0.8 ml / min</td><td>Flow rate 0.8 ml / min</td><td>Time 4.70 min 5% of B</td>

<td>Injection volume 2 pl</td><td>Injection volume 2 pl</td><td>Flow rate 0.8 ml / min</td>

<td></td><td></td><td>Injection volume 2 μΙ</td>

<td>Agilent 1200 HPLC / 1956 MSD / SEDEX 75 ELSD</td><td>Agilent 1200 HPLC / 1956 MSD / SEDEX 75 ELSD</td><td>Agilent 1200 HPLC / 1956 MSD / SEDEX 75 ELSD</td>

<td>APIES ionization mode</td><td>APIES ionization mode</td><td>APIES ionization mode</td>

<td>Polarity - Positive</td><td>Polarity - Positive</td><td>Polarity - Positive</td>

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<td rowspan="2">¹H NMR (400 MHz, dmso-d₆) δ 8.17-8.21 (m, 2 H) 7.90</td><td rowspan="2">- 7.91 (m, 2 H), 7.68 - 7.72 (m, 2 H), 7.43 - 7.44 (m, 1</td><td rowspan="2">H), 4.58-4.60 (m, 1 H), 4.18-4.22 (m, 1 H), 4.00 (s, 4</td><td rowspan="2">H), 2.68 (m, 1 H), 2.34 (m, 1 H), 1.47 - 1.48 (m, 1 H), 1.11-1.13 (d, 3H)</td><td rowspan="2">¹H NMR (400 MHz, CD₃OD) δ 8.23 ​​(m, 2 H), 7.78-7.80</td><td rowspan="2">(m, 1 H), 7.61 (m, 1 H), 7.25 - 7.26 (m, 1 H), 4.39 - 4.47</td><td rowspan="2">(m, 2 H), 4.04 - 4.05 (m, 1 H), 3.98 (s, 3 H), 2.63 - 2.65</td><td colspan="2">H), 1.12-1.14</td><td rowspan="2">¹H NMR (400 MHz, dmso-d₆) δ 8.04 (s, 1 H), 8.01 (s, 1</td><td rowspan="2">H), 7.75 - 7.79 (m, 2 H), 7.60 (s, 1 H), 7.52 (s, 1 H), 7.31</td><td rowspan="2">-7.32 (m, 1 H), 4.37-4.48 (m, 1 H), 4.17-4.22 (m, 1 H), 3.87 (s, 3 H), 3.55 - 3.58 (m, 1 H), 2.52 - 2.55 (m, 1</td><td rowspan="2">H), 1.97 - 2.03 (m, 1 H), 1.77 - 1.82 (m, 1 H), 1.46 - 1.50</td><td rowspan="2">(m, 1 H), 1.34 - 1.35 (m, 1 H), 0.79 - 0.83 (m, 3 H)</td>

<td>(m, 1 H), 2.27 (m, 1 H), 1.94 - 1.98 (m, 1</td><td>(d, 3 H)</td>

<td></td><td></td><td>or</td><td></td><td></td><td></td><td> 0</td><td></td><td></td><td></td><td></td><td>MT</td><td></td><td></td>

<td></td><td></td><td>CO</td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td></td><td> ^3</td><td></td><td></td>

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<td></td><td colspan="2">cm íj =</td><td></td><td></td><td>CM</td><td>HP</td><td></td><td></td><td></td><td></td><td>cm</td><td></td><td></td>

<td colspan="4"></td><td colspan="5"></td><td colspan="5"></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td>

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<td></td><td></td><td>V "</td><td></td><td></td><td></td><td>v—</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>CL</td><td></td><td></td><td></td><td>CL</td><td></td><td></td><td></td><td></td><td>X</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> \</td><td></td><td></td><td></td>

<td>jH</td><td></td><td> \</td><td>Y %</td><td> 17</td><td>&gt; —S</td><td></td><td>z-</td><td></td><td></td><td>Y</td><td></td><td></td><td></td>

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<td></td><td>OR</td><td></td><td> 2:</td><td></td><td>Z3 OR</td><td></td><td></td><td>z</td><td></td><td></td><td> ~ —0</td><td></td><td></td>

<td></td><td></td><td></td><td>X</td><td></td><td></td><td></td><td></td><td>X</td><td></td><td></td><td> '5</td><td>&gt; two: &lt;M</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>σ</td><td>X</td><td></td>

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