US 2010O3.31307A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0331307 A1 Salituro et al. (43) Pub. Date: Dec. 30, 2010
(54) THERAPEUTIC COMPOUNDS AND Publication Classification COMPOSITIONS (51) Int. Cl. (76) Inventors: Francesco G. Salituro, A 6LX 3/553 (2006.01) Marlborough, MA (US); Jeffrey O. A6IP35/00 (2006.01) Saunders, Concord, MA (US); A 6LX 3L/2197 (2006.01) Shunqi Yan, Irvine, CA (US) C07D 40/12 (2006.01) C07D 417/4 (2006.01) Correspondence Address: C07D 405/4 (2006.01) LANDO & ANASTASI, LLP C07D 40/4 (2006.01) ONE MAINSTREET, SUITE 1100 CAMBRIDGE, MA 02142 (US) (52) U.S. Cl...... 514/210.21; 514/218: 514/253.06; (21) Appl. No.: 12/826,630 540/575:544/363 Filed: Jun. 29, 2010 (22) (57) ABSTRACT Related U.S. Application Data Compounds and compositions comprising compounds that (60) Provisional application No. 61/221,430, filed on Jun. modulate pyruvate kinase M2 (PKM2) are described herein. 29, 2009, provisional application No. 61/292,360, Also described herein are methods of using the compounds filed on Jan. 5, 2010. that modulate PKM2 in the treatment of cancer. Patent Application Publication Dec. 30, 2010 Sheet 1 of 70 US 2010/0331307 A1
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THERAPEUTIC COMPOUNDS AND diseases and conditions that are related to pyruvate kinase COMPOSITIONS function (e.g., PKM2 function), including, e.g., cancer, dia betes, obesity, autoimmune disorders, and benign prostatic CLAIM OF PRIORITY hyperplasia (BPH). 0008. In one embodiment, provided is a pharmaceutical 0001. This application claims priority from U.S. Ser. No. composition comprising a compound or a pharmaceutically 61/221,430, filed Jun. 29, 2009 and U.S. Ser. No. 61/292,360, filed Jan. 5, 2010, each of which is incorporated herein by acceptable salt of formula (I): reference in its entirety. BACKGROUND OF INVENTION (I) R n (R), O 0002 Cancer cells rely primarily on glycolysis to generate L nN.1 W X D.n {A cellular energy and biochemical intermediates for biosynthe sis of lipids and nucleotides, while the majority of “normal' N Z A. cells in adult tissues utilize aerobic respiration. This funda N-8 2 / D mental difference in cellular metabolism between cancer cells and normal cells, termed the Warburg Effect, has been O exploited for diagnostic purposes, but has not yet been exploited for therapeutic benefit. 0009 wherein: 0003 Pyruvate kinase (PK) is a metabolic enzyme that 0010 W, X,Y and Zare each independently selected from converts phosphoenolpyruvate to pyruvate during glycolysis. CH or N: Four PK isoforms exist in mammals: the L and Risoforms are 10011. D and D'are independently selected from a bond or expressed in liver and red blood cells, the M1 isoform is NR; expressed in most adult tissues, and the M2 isoform is a splice 0012 A is optionally substituted aryl or optionally substi variant of M1 expressed during embryonic development. All tuted heteroaryl; tumor cells exclusively express the embryonic M2 isoform. A (0013 L is a bond, C(O)— —(CRR), OC well-known difference between the M1 and M2 isoforms of (O)— —(CRR), OC(O)— —(CRR), C(O) , PK is that M2 is a low-activity enzyme that relies on allosteric - NRC(S)-, or - NRC(O)- (wherein the point of the activation by the upstream glycolytic intermediate, fructose attachment to R' is on the left-hand side); 1,6-bisphosphate (FBP), whereas M1 is a constitutively I0014) R' is selected from alkyl, cycloalkyl, aryl, het active enzyme. eroaryl, and heterocyclyl; each of which is substituted with 0004 All tumor cells exclusively express the embryonic 0-5 occurrences of R". M2 isoform of pyruvate kinase, suggesting PKM2 as a poten I0015 each R is independently selected from halo, tial target for cancer therapy. PKM2 is also expressed in haloalkyl, alkyl, hydroxyl and —OR", or two adjacent R adipose tissue and activated T-cells. Thus, the modulation taken together with the carbon atoms to which they are (e.g. inhibition or activation) of PKM2 may be effective in the attached forman optionally substituted heterocyclyl; each R' treatment of, e.g., obesity, diabetes, autoimmune conditions, is independently selected from alkyl, acyl, hydroxyalkyl and and proliferation-dependent diseases, e.g., benign prostatic haloalkyl: hyperplasia (BPH). Current inhibitors of pyruvate kinase are (0016 each R is independently selected from hydrogen not selective, making it difficult to treat disease related to and alkyl, pyruvate kinase function. 0017 each R is independently selected from hydrogen, 0005. Furthermore, phosphotyrosine peptide binding to halo, alkyl, alkoxy and halo alkoxy or two R taken together PKM2 leads to a dissociation of FBP from PKM2 and con with the carbon atoms to which they are attached form an formational changes of PKM2 from an active, tetrameric optionally substituted cycloalkyl: form to an inactive form. Compounds that bind to PKM2 and 10018 each R" is independently selected from halo, lock the enzyme in the active confirmation will lead to the loss haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, of allosteric control of PKM2 needed for shunting biochemi C(O)R, OC(O)R’, C(O)OR', SR, NR'R'' and cal intermediates from glycolysis into biosynthesis of nucle —OR", or two R' taken together with the carbon atoms to otides and lipids. Thus, the activation of PKM2 (i.e., activa which they are attached form an optionally substituted het tors of PKM2) can also inhibit the growth and proliferation of erocyclyl, cancer cells, activated immune cells, and fat cells. 0019 n is 0, 1, or 2: 0006. There is a continuing need for novel treatments of 0020 m is 1, 2 or 3: diseases such as cancer, diabetes, obesity, autoimmune con 0021 h is 0, 1, 2; and ditions, proliferation-dependent diseases (e.g., BPH), and (0022 g is 0, 1 or 2. other diseases related to the function of pyruvate kinase (e.g., 0023. In another embodiment, provided is a method for PKM2). treating or preventing a disease, condition or disorder as described (e.g., treating) herein comprising administering a SUMMARY OF INVENTION compound provided herein, a pharmaceutically acceptable 0007. Described herein are compounds that modulate salt thereof, or pharmaceutical composition thereof. pyruvate kinase M2 (PKM2) and pharmaceutically accept 0024. In another embodiments, provided is a method of able salts, Solvates, and hydrates thereof, for example, com modulating (e.g., increasing or decreasing) the level of PKM2 pounds that activate PKM2. Also provided are pharmaceuti activity and/or glycolysis (e.g., modulating the endogenous cal compositions comprising a compound provided herewith ability of a cell in the patient to down regulate PKM2) in a and the use of Such compositions in methods of treating patient in need thereof. The method comprises the step of US 2010/0331307 A1 Dec. 30, 2010 administering an effective amount of a compound described pharmaceutical composition comprising a compound of for hereinto the patientin need thereof, thereby modulating (e.g., mula (I) or a pharmaceutically acceptable salt thereof: increasing or decreasing) the level of PKM2 activity and/or glycolysis in the patient. In some embodiments, a compound or a composition described herein is used to maintain PKM2 (I) in its active conformation or activate pyruvate kinase activity R! n (R), O in proliferating cells as a means to divert glucose metabolites L X DN / into catabolic rather than anabolic processes in the patient. nN.1 W S{ 0025. In another embodiment, provided is a method of N Z A. inhibiting cell proliferation in a patient in need thereof. The N-8 2 / D method comprises the step of administering an effective amount of a compound described hereinto the patient in need O thereof, thereby inhibiting cell proliferation in the patient. E.g., this method can inhibiting growth of a transformed cell, 0031 wherein: e.g., a cancer cell, or generally inhibiting growth in a PKM2 0032 W, X,Y and Zare each independently selected from dependent cell that undergoes aerobic glycolysis. CH or N: In another embodiment, provided is a method of treating a I0033 D and D" are independently selected from a bond or patient Suffering from or Susceptible to a disease or disorder NR; associated with the function of PKM2 in a patient in need 0034) A is optionally substituted aryl or optionally substi thereof. The method comprises the step of administering an tuted heteroaryl; effective amount of a compound described herein to the 0035 L is a bond, C(O)— —(CRR), OC patient in need thereof, thereby treating, preventing or ame (O)— —(CRR), OC(O) , —(CRR), C(O)—, liorating the disease or disorder in the patient. In certain - NRC(S)-, or - NRC(O)- (wherein the point of the embodiment the modulator is provided in a pharmaceutical attachment to R' is on the left-hand side); composition. In certain embodiment, the method includes 10036) R' is selected from alkyl, cycloalkyl, aryl, het identifying or selecting a patient who would benefit from eroaryl, and heterocyclyl; each of which is substituted with modulation (e.g., activation) of PKM2. E.g., the patient can 0-5 occurrences of R: be identified on the basis of the level of PKM2 activity inacell I0037 each R is independently selected from halo, of the patient for treatment of cancer associated with PKM2 haloalkyl, alkyl, hydroxyl and —OR", or two adjacent R function. In another embodiment, the selected patient is a taken together with the carbon atoms to which they are patient Suffering from or Susceptible to a disorder or disease attached form an optionally substituted heterocyclyl: identified herein, e.g., a disorder characterized by unwanted 0038 each R" is independently selected from alkyl, acyl, cell growth or proliferation, e.g., cancer, obesity, diabetes, hydroxyalkyl and haloalkyl: atherosclerosis, restenosis, and autoimmune diseases. I0039 each R is independently selected from hydrogen 0026. In another embodiment, the compound described and alkyl, herein is administered at a dosage and frequency Sufficient to 0040 each R is independently selected from hydrogen, increase lactate production or oxidative phosphorylation. halo, alkyl, alkoxy and halo alkoxy or two R taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl: BRIEF DESCRIPTION OF THE FIGURES I0041) each R" is independently selected from halo, 0027 FIG. 1 represents a table of exemplary compounds haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, and the corresponding activity of the compound. C(O)R, OC(O)R’, C(O)OR', SR, NR'R'' and —OR", or two R' taken together with the carbon atoms to which they are attached form an optionally substituted het DETAILED DESCRIPTION erocyclyl, 0028. The details of construction and the arrangement of 0042 n is 0, 1, or 2: components set forth in the following description or illus 0043 m is 1, 2 or 3: trated in the drawings are not meant to be limiting. Embodi 0044 h is 0, 1, 2; and ments can be practiced or carried out in various ways. Also, 0045 g is 0, 1 or 2. In certain embodiments, provided is a the phraseology and terminology used herein is for the pur compound of formula (I) or a pharmaceutically acceptable pose of description and should not be regarded as limiting. salt thereof: The use of “including.” “comprising, or “having.” “contain ing”, “involving, and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof (I) as well as additional items. R! (R), n L X DN / n N W n { Compounds N Z A. 0029 Described herein are compounds and compositions N-8 2 / D that modulate PKM2, for example, activate PKM2. Com pounds that modulate PKM2, e.g., activate PKM2, can be O used to treat disorders such as neoplastic disorders (e.g., cancer) or fat related disorders (e.g., obesity). 0046 wherein: 0030. In one embodiment, provided is a compound of 0047 W, X,Y and Zare each independently selected from formula (I) or a pharmaceutically acceptable salt thereof, or a CH or N: US 2010/0331307 A1 Dec. 30, 2010
I0048 D and D'are independently selected from a bond or 5-quinoxalinyl), optionally Substituted quinolinyl (e.g., NR; 4-quinolinyl or 8-quinolinyl), optionally Substituted cinnoli 0049 A is optionally substituted bicyclic heteroaryl; nyl (e.g., 8-cinnolinyl), optionally Substituted isoquinolinyl, 0050 L is a bond, C(O)— —(CRR), , OC optionally substituted indolyl (7-indolyl), optionally substi (O)— —(CRR), OC(O)— —(CRR), C(O) , tuted benzoxazolyl (e.g., 7-benzoxazolyl), optionally Substi NRC(S) , or NRC(O) ; tuted pyrrolopyridyl (e.g., 4-pyrrolopyridyl), optionally Sub I0051) R' is selected from alkyl, cycloalkyl, aryl, het stituted pyrrolopyrimidyl (e.g., 4-pyrrolopyrimidyl), eroaryl, and heterocyclyl; each of which is substituted with optionally substituted benzimidazolyl (e.g., 7-benzimida 0-5 occurrences of R: Zolyl), optionally Substituted benzthiazolyl (e.g., 4-benzthia I0052 each R is independently selected from halo, Zolyl, 2-methyl-4-benzthiazolyl or 7-benzthiazolyl), or haloalkyl, alkyl, hydroxyl and —OR or two adjacent R optionally Substituted benzoxazolyl (e.g., 4-benzoxazolyl). taken together with the carbon atoms to which they are In some embodiments, A is optionally substituted with halo. attached form an optionally substituted cyclyl; each R is In some embodiments, A is independently selected from alkyl, acyl, hydroxyalkyl and haloalkyl: I0053 each R is independently selected from hydrogen and alkyl, 0054 each R is independently selected from hydrogen, halo, alkyl, alkoxy and halo alkoxy or two R taken together with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; 0055 each R" is independently selected from halo, haloalkyl, haloalkoxy, alkyl, alkynyl, nitro, cyano, hydroxyl, C(O)R, OC(O)R, C(O)OR', SR, NR'R'' and In some embodiments, A is —OR", or two R' taken together with the carbon atoms to which they are attached form an optionally substituted het erocyclyl, 0056 n is 0, 1, or 2: 0057 m is 1, 2 or 3: 0058 h is 0, 1, 2; and 0059 g is 0, 1 or 2. In some embodiments, his 1. In some embodiments, h is 2. 0060. In some embodiments, g is 1. In some embodiments, g is 2. In some embodiments, A is optionally Substituted 0061. In some embodiments, both h and g are 1. In some embodiments, his 1 and g is 2. In some embodiments, g is 1 and h is 2. / N 0062. In some embodiments, W, X, Y and Z are CH. In some embodiments, at least one of W, X,Y and Z is N. In some embodiments, at least two of W, X, Y and Z are N. In some embodiments, at least three of W, X, Y and Z are N. 0063. In some embodiments, W, X,Y,Z and the carbons to +k) which they are attached form a pyridyl ring. In some embodi ments, W, X, Y, Z and the carbon atoms to which they are attached form a pyrimidyl ring. In some embodiments, W, X, In some embodiments, A is Y, Z and the carbon atoms to which they are attached form a pyridazinyl ring. 0064. In some embodiments, W, X and Y are CH and Z is / n N. 0065. In some embodiments, X,Y and Z are CH and W is N. C. I0066. In some embodiments, Dis NR' and D" is a bond. In some embodiments, D is a bond and D" is NR. In some - 3– embodiments, both D and D'are NR. In some embodiments, R’ is alkyl (e.g., methyl or ethyl). In some embodiments, Ris 0068. In some embodiments, L is a bond. hydrogen (H). 0069. In some embodiments, L is —(CRR), and m is 0067. In some embodiments, A is a 9-10 membered bicy 1. In some aspects of these embodiments, each R is hydro clic heteroaryl (e.g., quinazolinyl, quinoxalinyl, cinnolinyl, gen. In some aspects of these embodiments, one R is alkyl isoquinolyl, indolyl, benzoxazolyl pyrrolopyridyl, pyrrol (e.g., methyl or ethyl) and the other R is hydrogen. In some opyrimidyl, benzimidazolyl, benzthiazolyl, or benzox aspects of these embodiments, one R is halo (e.g., fluoro) and azolyl). In some embodiments, A is a N-containing 9-10 one R is hydrogen. In some aspects of these embodiments, membered bicyclic heteroaryl. In some embodiments, A is both R are halo (e.g., fluoro). In some aspects of these optionally Substituted quinazolinyl (e.g., 8-quinazolinyl or embodiments, one R is alkoxy (e.g., methoxy or ethoxy) and 4-quinazolinyl), optionally Substituted quinoxalinyl (e.g., one R is hydrogen. In some aspects of these embodiments, US 2010/0331307 A1 Dec. 30, 2010 both R are alkoxy (e.g., methoxy or ethoxy). In some aspects pyrimidyl substituted with 0-5 occurrences of R" (e.g., 2-py of these embodiments, two R taken together with the carbon rimidyl or 5-pyrimidyl) or pyrazinyl substituted with 0-5 to which they are attached form a cycloalkyl (e.g., cyclopro occurrences of R (e.g., 2-pyrazinyl). In some embodiments, pyl). R" is thiazolyl substituted with 0-5 occurrences of R (e.g., 0070. In some embodiments, L is —(CRR), and m is 2-thiazolyl or 5-thiazolyl). In some embodiments, R' is 2. In some aspects of these embodiments, each R is hydro pyrimidyl substituted with 0-5 occurrences of R (e.g., 2-py gen. In some aspects of these embodiments, 1 R is alkyl (e.g., rimidyl). In some embodiments, R' isthiadiazolyl substituted methyl or ethyl) and each of the other R are hydrogen. In with 0-5 occurrences of R (e.g., 4-thiadiazolyl). In some Some aspects of these embodiments, two Rs taken together embodiments, R is pyrrolyl substituted with 0-5 occurrences with the carbon to which they are attached form a cycloalkyl of R (e.g., 2-pyrrolyl). In some aspects of these embodi (e.g., cyclopropyl) and each of the other two Rs are hydro ments, L is a bond, —CH2—, —C(O)—, or —O(CO)—. In gen. some embodiments, R' is pyridyl (e.g., 2-pyridyl, 3-pyridyl 0071. In some embodiments, L is —(CRR), and m is or 4-pyridyl). 3. In some aspects of these embodiments each R is hydrogen. I0082 In some embodiments, R is pyridyl (e.g., 2-pyridyl, 0072. In some embodiments, L is —C(O)—. 3-pyridyl or 4-pyridyl) substituted with 1 occurrence of R". In 0073. In some embodiments, L is —O—C(O)—. some aspects of these embodiments, R is —OC(O)R". In 0074. In some embodiments, L is NRC(O)—and R is H. some aspects of these embodiments, R is OR". In some In some embodiments, L is NRC(S)- and R is H. aspects of these embodiments, R is —C(O)OR". In some 0075. In some embodiments, L is —(CRR), C(O)— aspects of these embodiments, R is alkyl (e.g., methyl or and m is 1. In some aspects of these embodiments, each R is ethyl). In some aspects of these embodiments, Rishaloalkyl hydrogen. In some aspects of these embodiments, one R is (e.g., trifluoromethyl). In some aspects of these embodi alkyl (e.g., methyl or ethyl) and one R is hydrogen. In some ments, R is halo (e.g., fluorine or chlorine). In some aspects aspects of these embodiments, both R are alkyl (e.g., methyl of these embodiments, R is alkyl (e.g., methyl or ethyl). In or ethyl). Some aspects of these embodiments, L is —CH2—. In some 0076. In some embodiments, L is —(CRR), C(O)— embodiments, R' is pyridyl (e.g., 2-pyridyl, 3-pyridyl or and m is 2. In some aspects of these embodiments, each R is 4-pyridyl) substituted with 2 occurrences of R". In some hydrogen. aspects of these embodiments, one R is C(O)CR" and the 0077. In some embodiments, L is —(CRR), C(O)— other Ris—OR". In some aspects of these embodiments, R and m is 3. In some aspects of these embodiments, each R is is alkyl (e.g., methyl or ethyl). In some aspects of these hydrogen. embodiments, both R" are halo (e.g., fluoro or chloro). In I0078. In some embodiments, R' is alkyl substituted with Some aspects of these embodiments, L is —CH2 . 0-5 occurrences of R (e.g., methyl, ethyl, n-propyl, i-propyl, I0083. In some embodiments, R' is pyrimidyl (e.g., 2-py or n-butyl). In some embodiments, R' is methyl, ethyl, n-pro rimidyl or 5-pyrimidyl). In some aspects of these embodi pyl, i-propyl, or n-butyl. In some embodiments, R' is ethyl or ments, L is a bond. propyl (n-propyl or i-propyl). In some aspects of these I0084. In some embodiments, R is pyrimidyl (e.g., 2-py embodiments, L is a bond, —CH2—, —C(O)—, or rimidyl or 5-pyrimidyl) substituted with 1 occurrence of R". —O(CO)—. In some aspects of these embodiments, L is In some aspects of these embodiments, Rishalo (e.g., fluoro –O(CO)-. or chloro). 0079. In some embodiments, R is alkyl substituted with 1 I0085. In some embodiments, R' is pyrazinyl (e.g., occurrence of R' (e.g., methyl ethyl, n-propyl, i-propyl, or 2-pyrazinyl). In some aspects of these embodiments, L is a n-butyl). In some embodiments, R' is methyl, ethyl, or n-pro bond. pyl substituted with 1 occurrence of R". In some aspects of I0086) In some embodiments, R' is thiazolyl (e.g., 2-thia these embodiments, R is halo (e.g., fluorine or chlorine). In Zolyl, 4-thiazolyl, or 5-thiazolyl). In some aspects of these some aspects of these embodiments, R is C(O)OR". In embodiments, L is —C(O)—. Some aspects of these embodiments, R is alkyl (e.g., methyl I0087. In some embodiments, R' is thiazolyl (e.g., 2-thia or ethyl). In some aspects of these embodiments, L is NHC Zolyl, 4-thiazolyl, or 5-thiazolyl) substituted with 1 occur (O)—. rences of R". In some aspects of these embodiments, R is 0080. In some embodiments, R is alkyl substituted with 2 alkyl (e.g., methyl or ethyl). In some aspects of these embodi occurrences of R (e.g., methyl ethyl, n-propyl, i-propyl, or ments, L is —C(O)—. n-butyl). In some embodiments, R' is methyl, ethyl, or n-pro I0088. In some embodiments, R is thiophenyl substituted pyl substituted with 2 occurrences of R". In some embodi with 0-5 occurrences of R (e.g., 2-thiophenyl). In some ments, R' is n-propyl substituted with 2 occurrences of R". In embodiments, R is thiophenyl. some aspects of these embodiments, 1 R is cyano and the I0089. In some embodiments, R is thiadiazolyl (e.g., other R is NR'R''. In some aspects of these embodiments, 4-thiadiazolyl). R" and Rare hydrogen. In some aspects of these embodi I0090. In some embodiments, R' is pyrrolyl (e.g., 2-pyrro ments, L is —CH2—. lyl). I0081. In some embodiments, R' is heteroaryl substituted I0091. In some embodiments, R' is cycloalkyl substituted with 0-5 occurrences of R (e.g., S-containing monocyclic with 0-5 occurrences of R' (e.g., cyclopropyl, cyclopentylor heteroaryl. N-containing monocyclic heteroaryl or N-con cyclohexyl). In some embodiments, R' is cyclopropyl. In taining bicyclicheteroaryl). In some embodiments, R' is a 5-8 Some embodiments, R' is cyclohexyl. In some embodiments, membered monocyclic heteroaryl substituted with 0-5 occur R" is cyclopentyl. In some aspect of these embodiments, L is rences of R' (e.g., thiophenyl, pyridyl, pyrimidyl or pyrazyl). —CH C(O)—. In some embodiment, R' is aryl substituted In some embodiments, R' is pyridyl substituted with 0-5 with 0-5 occurrences of R". In some aspects of these embodi occurrences of R (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), ments, L is a bond, —CH2—, —C(O)—, or —O(CO) US 2010/0331307 A1 Dec. 30, 2010
0092. In some embodiments R' is aryl (e.g., phenyl). In Some embodiments, R' is phenyl. In some aspects of these embodiments, L is a bond, —CH2—, —C(O)—, or –O(CO)-. I0093. In some embodiments, R' is phenyl substituted with 1 occurrence of R". In some aspects of these embodiments, R' S is ortho Substituted. In some aspects of these embodiments, R" is meta substituted. In some aspects of these embodiments, R" is para substituted. In some aspects of these embodiments, R" is halo (e.g., fluorine, bromine or chlorine). In some aspects of these embodiments, R is alkyl (e.g., methyl ethyl, In some aspects of these embodiments, R is alkyl (e.g., isopropyl, t-butyl, n-butyl or n-pentyl). In some aspects of methyl or ethyl). In some aspects of these embodiments, L is these embodiments, R is haloalkyl (e.g., trifluoromethyl). In a bond, —CH2—, —C(O)—, or —O(CO) some aspects of these embodiments, R is OR". In some I0095. In some embodiments, R is phenyl substituted with aspects of these embodiments, R is C(O)R". In some 3 occurrences of R". In some aspects of these embodiments, aspects of these embodiments, R is - SR". In some aspects 3 R' are halo (e.g., fluorine or chlorine). In some aspects of of these embodiments, R is —C(O)CR". In some aspects of these embodiments, 2 R are halo (e.g., fluorine or chlorine) these embodiments, R is cyano. In some aspects of these and 1 R is hydroxyl. In some aspects of these embodiments, embodiments, R is NR'R''. In some aspects of these 1 R is halo (e.g., fluorine or chlorine), 1 R is alkyl (e.g., embodiments, R is haloalkoxy (e.g., difluoromethoxy or tri methyl) and 1 R is hydroxyl. In some aspects of these fluoromethoxy). In some aspects of these embodiments, Ris embodiments, 3 R' are alkyl (e.g., methyl or ethyl). In some hydroxyl. In some aspects of these embodiments, R is —OC aspects of these embodiments, 2 R are alkyl (e.g., methyl or (O)R". In some aspects of these embodiments, R is alkynyl ethyl) and 1 R is hydroxyl. In some aspects of these embodi (e.g., 1-hexynyl). In some aspects of these embodiments, R' ments, 2 R are halo (e.g., fluorine or chlorine) and 1 R is is haloalkyl (e.g., trifluoromethyl). In some aspects of these —OR". In some aspects of these embodiments, R is alkyl embodiments, R is alkyl (e.g., methyl, ethyl, n-propyl, iso (e.g., methyl or ethyl). In some aspects of these embodiments, propyl. n-butyl, isobutyl, t-butyl or n-pentyl). In some aspects 1 R is hydroxyland 2 R are -OR". In some aspects of these of these embodiments, R is hydroxyalkyl (e.g., 2-hydroxyl ethyl). In some aspects of these embodiments, R" and Rare embodiments, R is alkyl (e.g., methyl or ethyl). In some alkyl (e.g., methyl or ethyl). In some aspects of these embodi aspects of these embodiments, 3 R' are OR". In some ments, R is acyl (e.g., acetyl) and R is hydrogen. In some aspects of these embodiments, 3 R' are halo (e.g., fluorine or aspects of these embodiments, L is a bond, —CH2—, chlorine). In some aspects of these embodiments, R is alkyl —C(O)—, or —O(CO)—. (e.g., methyl or ethyl). In some aspects of these embodiments, I0094) In some embodiments, R' is phenyl substituted with L is a bond, —CH2—, —C(O)—, or —O(CO) 2 occurrences of R". In some aspects of these embodiments, I0096) In some embodiments, R' is phenyl substituted with both R" are halo (e.g., fluorine orchlorine). In some aspects of 4 occurrences of R". In some aspects of these embodiments, these embodiments, both R" are alkyl (e.g., methyl or ethyl). 1 R is hydroxyl, 1 R is alkyl (e.g., methyl or ethyl) and 2 R' In some aspects of these embodiments, 1 R is alkyl (e.g., are —OR". In some aspects of these embodiments, R is alkyl methyl or ethyl) and the other is —OR". In some aspects of (e.g., methyl or ethyl). In some aspects of these embodiments, these embodiments, 1 R is halo (e.g., fluorine or chlorine) L is a bond, —CH2—, —C(O)—, or —O(CO) and the other R is —OR". In some aspects of these embodi I0097. In some embodiments, R' is heterocyclyl substi ments, both R" are —OR". In some aspects of these embodi tuted with 0-5 occurrences of R". ments, 1 R is halo (e.g., fluorine orchlorine) and the other R' is hydroxyl. In some aspects of these embodiments, 1 R is I0098. In some embodiments, R' is tetrahydrofuranyl sub halo (e.g., fluorine or chlorine) and the other is haloalkyl (e.g., stituted with 0-5 occurrences of R (e.g., 2-tetrahydrofuranyl trifluoromethyl). In some aspects of these embodiments, 1 R' or 3-tetrahydrofuranyl). In some aspects of these embodi is —OR" and the other Ris—C(O)CR". In some aspects of ments, R' is tetrahydrofuranyl (e.g., 2-tetrahydrofuranyl or these embodiments, 1 R is —OR" and the other R is 3-tetrahydrofuranyl). In some aspects of these embodiments, hydroxyl. In some aspects of these embodiments, 1 R is alkyl L is —C(O)—. (e.g., methyl or ethyl) and the other R is hydroxyl. In some I0099. In some embodiments, R' is azetidinyl substituted aspects of these embodiments, both R" are hydroxyl. In some with 0-5 occurrences of R' (e.g., 3-azetidinyl). In some aspects of these embodiments, 1 R is halo (e.g., fluorine) and embodiments, R' is azetidinyl (e.g., 3-azetidinyl). In some the other R is haloalkyl (e.g., trifluoromethyl). In some embodiments, R' is azetidinyl (e.g., 3-azetidinyl) substituted aspects of these embodiments, both R" are hydroxyl. In some with 1 occurrence of R". In some aspects of these embodi aspects of these embodiments, one R is haloalkyl (e.g., trif ments, R is alkyl (e.g., methyl or ethyl). In some aspects of luoromethyl) and the other R is alkyl (e.g., methyl). In some aspects of these embodiments, two R', together with the these embodiments, L is —C(O)—. carbon atoms to which they are attached, form an optionally 10100. In some embodiments, R' is 10-14 membered bicy substituted heterocyclyl. In some aspects of these embodi clic aryl substituted with 0-5 occurrences of R". In some ments, two R', together with the carbonatoms to which they embodiments, R is naphthyl substituted with 0-5 occur are attached, form an optionally substituted 5-7 membered rences of R". In some embodiments, R is naphthyl. heterocyclyl. In some aspects of these embodiments, two R', I0101. In some embodiments, L is a bond, —(CRR), , together with the phenyl ring to which they are attached, form - NRC(O)— —(CRR), C(O) , —C(O) , or the following structure: - O(CO)-. US 2010/0331307 A1 Dec. 30, 2010
I0102) In some embodiments, L is a bond and R' is alkyl, 0112. In certain embodiments, a compound is of formula aryl or heteroaryl substituted with 0-5 occurrences of R". In (II) or a pharmaceutical acceptable salt thereof: Some aspects of these embodiments, alkyl, aryl or heteroaryl of R' is as described in any one of the embodiments and aspects above. (II) (0103) In some embodiments, L is —(CRR), and R' is RI n (R), O cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with L X D 0-5 occurrences of R". In some aspects of these embodiments, st t n ? cycloalkyl, aryl, heteroaryl or heterocyclyl of R' is as N 2 O described in any one of the embodiments and aspects above. N- 2 I0104. In some embodiments, L is NRC(O)—and R is hydrogen; and R' is aryl substituted with 0-5 occurrences of R". In some aspects of these embodiments, aryl of R is as described in any one of the embodiments and aspects above. wherein L, R, R. R. R. R. R. Y, Z, m, h and g are as In some embodiments, L is —(CRR), C(O) and R' is defined above informula (I) or any one of the embodiments or cycloalkyl, aryl or heteroaryl substituted with 0-5 occur aspects described herein. rences of R". In some aspects of these embodiments, 0113. In certain embodiments, A is aryl (e.g., phenyl or cycloalkyl, aryl, or heteroaryl of R is as described in any one naphthyl) optionally substituted with 1 or 2 occurrences of of the embodiments and aspects above. R, wherein each R is independently selected from halo, haloalkyl, aryl, heteroaryl, alkyl, —OR, COOR, or 0105. In some embodiments, L is C(O)—and R' is aryl, CONRR and D, D, L, R,R,R,R,R,R, X,Y,Z, W, alkyl, or heteroaryl substituted with 0-5 occurrences of R". In n, m, hand g are as defined above informula (I) or any one of Some aspects of these embodiments, aryl, alkyl, or heteroaryl the embodiments or aspects described herein. In some aspect of R' is as described in any one of the embodiments and of these embodiments, D and D" are N. In some aspect of aspects above. these embodiments, at least one of W, X,Y and Zis N. In some 0106. In some embodiments, L is —OC(O)— and R' is aspect of these embodiments, one of W, Y and Z is N: h is 1 and g is 1. alkyl, aryl or heterocyclyl substituted with 0-5 occurrences of 0114. In certain embodiments, A is heteroaryl (e.g., R". In some aspects of these embodiments, alkyl, aryl, or N-containing monocyclic heteroaryl or N-containing bicyclic heterocyclyl of R is as described in any one of the embodi heteroaryl); and D, D, L, R, R,R,R,R,R, X, Y, Z, W, ments and aspects above. n, m, hand g are as defined above informula (I) or any one of 0107. In some embodiments, L is —(CRR), OC(O)— the embodiments or aspects described herein. In some and R' is heterocyclyl or cycloalkyl substituted with 0-5 embodiments, A is a 5-8 membered monocyclic heteroaryl occurrences of R". In some aspects of these embodiments, (e.g., pyridyl, pyrimidyl, or pyrazyl); and D, D', L, R,R,R, heterocyclyl or cycloalkyl of R' is as described in any one of R. R. R. X, Y, Z. W, n. m., hand g are as defined above in formula (I) or any one of the embodiments or aspects the embodiments and aspects above. described herein. In some embodiments, A is a 5-8 membered 0108. In some embodiments, n is 0. In some embodiments, N-containing monocyclic heteroaryl; and D, D', L, R', R, n is 1. R. R. R. R. X, Y, Z, W, n. m, hand g are as defined above 0109. In some embodiments, R is alkyl (e.g., methyl or in formula (I) or any one of the embodiments or aspects described herein. In some embodiments, A is optionally Sub ethyl). In some embodiments, R is —OR". In some aspects stituted pyridyl (e.g., 2-pyridyl, 3-pyridyl or 4-pyridyl), of these embodiments, R is alkyl (e.g., methyl or ethyl). In optionally Substituted pyrimidyl (e.g., 2-pyrimidyl or 5-py Some embodiments, R is halo (e.g., fluorine or chlorine). In rimidyl), or optionally Substituted pyrazyl (e.g., 2-pyrazyl); some embodiments, R is hydroxyl. In some embodiments, and L, R, R. R. R. R. R.Y. Z. m., hand g are as defined R is haloalkyl (e.g., trifluoromethyl). above informula (I) or any one of the embodiments or aspects 0110 In some embodiments, n is 2. described herein. 0.115. In some embodiments, A is substituted with 1 occur 0111. In some embodiments, two adjacent R taken rence of R: and D, D, L, R,R,R,R,R,R, X,Y,Z, W. together with the carbon atoms to which they are attached n, m, hand g are as defined above informula (I) or any one of form a heterocyclyl ring. In some embodiments, both Rare the embodiments or aspects described herein. In some aspects —OR". In some embodiments, two adjacent R taken of these embodiments, R is alkyl (e.g., methyl or ethyl). In together with the carbon atoms to which they are attached Some aspects of these embodiments, R is halo. In some form aspects of these embodiments, R is fluorine (F). In some aspects of these embodiments, R is bromine (Br). In some aspects of these embodiments, R is chlorine (Cl). In some aspects of these embodiments, R is —OR". In some aspects O O of these embodiments, R is alkyl (e.g., methyl). 0116. In some embodiments, A is substituted with 2 occur rences of R: and D, D, L, R,R,R,R,R,R, X,Y,Z, W. n, m, hand g are as defined above informula (I) or any one of the embodiments or aspects described herein. In some aspects of these embodiments, both R are halo (e.g., fluorine or fluorine and chlorine). In some aspects of these embodiments, US 2010/0331307 A1 Dec. 30, 2010 both R are alkyl (e.g. methyl). In some aspects of these I0128 each R" is independently selected from halo, embodiments, both R are —OR". In some aspects of these haloalkyl, alkyl, nitro, cyano and —OR", or two R' taken embodiments, one R is halo and the otheris—OR". In some together with the carbon atoms to which they are attached aspects of these embodiments, one R is bromine (BR) and form an optionally substituted heterocyclyl: the other is —OR". In some aspects of these embodiments, 0129 n is 0, 1, or 2: one R is chlorine (Cl) and the other is —OR". In some 0.130 m is 1, 2 or 3: aspects of these embodiments, one R is fluorine (F) and the 0131 h is 0, 1, 2; and other is —OR". In some aspects of these embodiments, R is I0132 g is 0, 1 or 2. In some aspects of this embodiment, A, alkyl (e.g., methyl or ethyl). In some aspects of these embodi D, D, L. R. R. R. R. R. R. X,Y,Z, W, n. m., hand g are ments, both R are —OR". In some aspects of these embodi as defined in any one of the embodiments or aspects described ments, two —OR” taken together with the carbon atoms to herein. which they are attached form a heterocyclyl. In some embodi I0133. In another embodiment, provided is a compound of ments, A is formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of for mula (I) or a pharmaceutically acceptable salt thereof: xO.) (I) and D, D, L, R,R,R,R,R,R, X, Y, Z, W, n. m., hand N gareas defined above informula (I) or any one of the embodi Y ments or aspects described herein. O 0117. In another embodiment, provided is a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of for 0.134 wherein: mula (I) or a pharmaceutically acceptable salt thereof: 0.135 W, X,Y and Zare each independently selected from CH or N: 10136) D and D'are independently selected from a bond or (I) NR; 3 0.137 A is optionally substituted aryl or optionally substi tuted heteroaryl; RN nN.1 w\"s1"S'N. D / I0138) R' is independently selected from alkyl, optionally N Z A. substituted aryl, and optionally substituted heteroaryl; N-8 2 / D I0139 each R is independently selected from halo, haloalkyl, alkyl, and —OR': O 0140 each R" is independently selected from alkyl, haloalkyl and optionally substituted heteroaryl; 0118 wherein: I0141 each R is independently alkyl: 0119 W, X,Y and Z are each independently selected from 0.142 each R is independently selected from hydrogen or CH or N: alkyl: 0120 D and D" are independently selected from a bond or 0.143 n is 0, 1, or 2: NR; 0.144 h is 0, 1, 2; and 0121 A is optionally substituted aryl or optionally substi 0145 g is 0, 1 or 2. In some aspects of this embodiment, A, tuted heteroaryl; D, D, L, R,R,R,R,R,R, X, Y, Z, W, n. m, hand g are 0122 L is a bond, —C(O)— —(CRR), , —OC as defined in any one of the embodiments or aspects described (O) , or - C(O)NR' : herein. (0123 R' is independently selected from alkyl, cycloalkyl, 0146 In another embodiment, provided is a compound or aryl, heteroaryl, and heterocyclyl; each of which are substi pharmaceutically acceptable salt of formula (Ib) or a pharma tuted with 0-3 occurrences of R". ceutical composition comprising a compound or pharmaceu I0124 each R is independently selected from halo, tically acceptable salt of formula (Ib): haloalkyl, alkyl, hydroxyl and —OR" or two adjacent R taken together with the carbon atoms to which they are (Ib) attached form an optionally Substituted cyclyl; 0.125 each R" is independently selected from alkyl and R! n f O haloalkyl: L nN.1 w1NX NNS{ / I0126) each R is independently selected from hydrogen WYA, and alkyl, N 27, O 0127 each R is independently selected from hydrogen, 8 halo, alkyl, alkoxy and halo alkoxy or two R taken together O R3 with the carbon atoms to which they are attached form an optionally substituted cycloalkyl; US 2010/0331307 A1 Dec. 30, 2010 wherein A, L, R,R,R,R,R,R, W, X, Z, m, hand g are wherein A, L,R,R,R,R,R,R, W, X,Y,Z, m, handgare as defined above informula (I) or any one of the embodiments as defined above informula (I) or any one of the embodiments or aspects described herein. or aspects described herein. 0147 In some embodiments, X, W and Z are CH. In some 0153. In certain embodiments, exemplary compounds of embodiments, one of X, W and Z is N and the other two of X, Formula I include the compounds described in FIG. 1 and in W and Z are CH. the Examples. In some embodiments, a compound described 0148. In another embodiment, provided is a pharmaceuti herein modulates PKM2 by interacting (e.g., binding) with cal composition comprising a compound orpharmaceutically the FBP binding pocket. For example, a compound described acceptable salt of formula (Ic) or a pharmaceutical composi herein can compete with FBP binding in PKM2. tion comprising a compound or pharmaceutically acceptable 0154) In some embodiments a compound described herein salt of formula (Ic): has one or more properties described herein, e.g., one or more of the following properties: it is an allosteric modulator (e.g., activator); it modulates the release of FBP (e.g., promotes); it (Ic) is a modulator (e.g., agonist) of FBP, e.g., an agonist which Rb binds with a lower, about the same, or higher affinity than O R's L X does FBP: it modulates (e.g., promotes) the dissolution of YN w1N NSAS tetrameric PKM2; it modulates (e.g., promotes) the assembly W YA of tetrameric PKM2; it selectively modulates (e.g., activates) N 2 O PKM2 over at least one other isoform of PK, e.g., it is selec g Y R3 tive for PKM2 over PKR, PKM1, or PKL is has an affinity for O PKM2 which is greater than its affinity for at least one other isoform of PK, e.g., PKR, PKM1, or PKL. 0.155. In another embodiment, the activator of PKM2 uti wherein A. L. R. R. R. R. R. R. W, X, Y, m, hand g are lized in the methods and compositions described herein oper as defined above informula (I) or any one of the embodiments ates by or has one or more of the following mechanisms or or aspects described herein. properties: 0149. In some embodiments, X,Y and Ware CH. In some 0156 a. it is an allosteric activator of PKM2: embodiments, one of X,Y and W is N and the other two of X, 0157 b. it modulates (e.g., stabilizes) the binding of Y and W are CH. FBP in a binding pocket of PKM2: 0150. In another embodiment, provided is a compound or 0158 c. it modulates (e.g., promotes) the release of FBP pharmaceutically acceptable salt of formula (Id) or a pharma from a binding pocket of PKM2; ceutical composition comprising a compound or pharmaceu 0159 d. it is a modulator (e.g., an agonist), e.g., an tically acceptable salt of formula (Id): analog, of FBP. e.g., an agonist which binds PKM2 with a lower, about the same, or higher affinity than does FBP: (Id) 0.160 e. it modulates (e.g., promotes) the dissolution of tetrameric PKM2; 0.161 f. it modulates (e.g., promotes) the assembly of tetrameric PKM2; 0162 g. it modulates (e.g., stabilizes) the tetrameric conformation of PKM2; 0.163 h. it modulates (e.g., promotes) the binding of a phosphotyrosine containing polypeptide to PKM2; 0.164 i. it modulates (e.g., promotes) the ability of a wherein A. L. R. R. R. R. R. R. Y. Z. m., hand g are as phosphotyrosine containing polypeptide to induce defined above informula (I) or any one of the embodiments or release of FBP from PKM2, e.g., by inducing a change in aspects described herein. the conformation of PKM2, e.g., in the position of Lys 0151. In some embodiments, Y and Z are CH. In some 433, thereby hindering the release of FBP: embodiments, one ofY and Z is N and one ofY and Z is CH. 0.165 k. it binds to or changes the position of Lys 433 0152. In another embodiment, provided is a compound or relative to the FBP binding pocket; pharmaceutically acceptable salt of formula (Ie) or a pharma 0166 1. it selectively modulates (e.g., activates) PKM2 ceutical composition comprising a compound or pharmaceu over at least one other isoform of PK, e.g., it is selective tically acceptable salt of formula (Ie): for PKM2 over one or more of PKR, PKM1, or PKL 0.167 m. it has an affinity for PKM2 which is greater than its affinity for at least one other isoform of PK, e.g., (Ie) PKR, PKM1, or PKL. R! n Na" O L X N 0168 A compound described herein may be tested for its n- w1N S{ ability to activate PKM2. For simplicity, the activation activ ity of these compounds is represented as an ACso in FIG. 1 N- N 2Z. / A: and throughout the application. Exemplary compounds are 8 2 shown in FIG.1. As shown in FIG.1, “A” refers to an activator O of PKM2 with an ECs-100 nM. “B” refers to an activator of PKM2 with an ECso between 100 nM and 500 nM. “C” refers to an activator of PKM2 with an ECso between 500 nM and US 2010/0331307 A1 Dec. 30, 2010
1000 nM. “D” refers to an activator of PKM2 with an ECso acid 4. piperazine (5) is with the appropriate bromide under between 1 uM and 10 uM.. “E” refers to data that is not standard palladium coupling conditions to provide 7. Car available. boxylic acid 4 is then treated with piperazine derivative 7 to 0169. The compounds described herein can be made using produce final compound 8. a variety of synthetic techniques. 0171 As can be appreciated by the skilled artisan, meth ods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Addition Scheme 1. ally, the various synthetic steps may be performed in an NH2 alternate sequence or order to give the desired compounds. O\/ O Synthetic chemistry transformations and protecting group N1 No N pyridine, DCM methodologies (protection and deprotection) useful in Syn -- (R), thesizing the compounds described herein are known in the A. 2 21 art and include, for example, those Such as described in R. (R2) Larock, Comprehensive Organic Transformations, VCH COOEt Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective 1 2 Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons O (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. 21 OEt Paquette, ed., Encyclopedia of Reagents for Organic Synthe O\/ O LiOHIHO sis, John Wiley and Sons (1995), and subsequent editions N NN SX thereof. H (R), 0172. The compounds provided herein may contain one or more asymmetric centers and thus occur as racemates and 2 racemic mixtures, single enantiomers, individual diastere (R2) omers and diastereomeric mixtures. All Such isomeric forms 3 of these compounds are expressly included within the Scope. COOH Unless otherwise indicated when a compound is named or O O 21 depicted by a structure without specifying the stereochemis \/ try and has one or more chiral centers, it is understood to N NN SX represent all possible stereoisomers of the compound. The H (R), compounds provided herewith may also contain linkages A-4 (e.g., carbon-carbon bonds) or Substituents that can restrict (R2) bond rotation, e.g. restriction resulting from the presence of a 4 ring or double bond. Accordingly, all cis/trans and E/Z iso R-Br mers are expressly included. - Pd(OAc), - 0173 The compounds provided herein (e.g. of Formula I) may also comprise one or more isotopic Substitutions. For HN NH - CsCO3,BNA - HN N-R,I -->HATU example, H may be in any isotopic form, including 'H, H(D \ / dioxane \ / NMM or deuterium), and H (Tortritium); C may be in any isotopic 5 7 DMF, form, including 'C, C, and ''C: O may be in any isotopic rt, 12 h. form, including 'O and 'O; and the like. The compounds oy- (R)n provided herein may also be represented in multiple tauto meric forms, in Such instances, expressly includes all tauto meric forms of the compounds described herein, even though saO only a single tautomeric form may be represented (e.g., alky cav lation of a ring system may result in alkylation at multiple N sites; all such reaction products are expressly included). All Such isomeric forms of Such compounds are expressly included. All crystal forms of the compounds described herein are expressly included. / \ = 7 (R), 0.174. The compounds provided herein include the com R- N pounds themselves, as well as their salts and their prodrugs, if applicable. A salt, for example, can be formed between an \ / Y, anion and a positively charged substituent (e.g., amino) on a 8 compound described herein. Suitable anions include chlo R, R2, R, m and n = as defined herein ride, bromide, iodide, Sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, a salt can also be formed between a cation and a negatively 0170 Scheme 1 above is an exemplary scheme that charged Substituent (e.g., carboxylate) on a compound depicts a representative synthesis of certain compounds described herein. Suitable cations include Sodium ion, potas described herein. Sulfonyl chloride 1 is reacted with amine 2 sium ion, magnesium ion, calcium ion, and an ammonium under standard coupling conditions to produce ester 3. cation Such as tetramethylammonium ion. Examples of pro Hydrolysis of 3 using lithium hydroxide generates carboxylic drugs include esters and other pharmaceutically acceptable US 2010/0331307 A1 Dec. 30, 2010
derivatives, which, upon administration to a Subject, are or “aralkyl refer to an alkyl moiety in which an alkyl hydro capable of providing active compounds. gen atom is replaced by an aryl group. Aralkyl includes 0.175. The compounds provided herein may be modified groups in which more than one hydrogen atom has been by appending appropriate functionalities to enhance selected replaced by an aryl group. Examples of “arylalkyl or biological properties, e.g., targeting to a particular tissue. “aralkyl include benzyl, 2-phenylethyl 3-phenylpropyl. Such modifications are known in the art and include those 9-fluorenyl, benzhydryl, and trityl groups. which increase biological penetration into a given biological 0179 The term “alkylene' refers to a divalent alkyl, e.g., compartment (e.g., blood, lymphatic system, central nervous —CH2—, —CH2CH2—, and —CH2CH2CH2—. system), increase oral availability, increase solubility to allow 0180. The term “alkenyl refers to a straight or branched administration by injection, alter metabolism and alter rate of hydrocarbon chain containing 2-12 carbon atoms and having excretion. one or more double bonds. Examples of alkenyl groups 0176). In an alternate embodiment, the compounds include, but are not limited to, allyl, propenyl, 2-butenyl, described herein may be used as platforms or scaffolds that 3-hexenyl and 3-octenyl groups. One of the double bond may be utilized in combinatorial chemistry techniques for carbons may optionally be the point of attachment of the preparation of derivatives and/or chemical libraries of com alkenyl substituent. The term “alkynyl refers to a straight or pounds. Such derivatives and libraries of compounds have branched hydrocarbon chain containing 2-12 carbon atoms biological activity and are useful for identifying and design and characterized in having one or more triple bonds. ing compounds possessing a particular activity. Combinato Examples of alkynyl groups include, but are not limited to, rial techniques suitable for utilizing the compounds described ethynyl, propargyl, and 3-hexynyl. One of the triple bond herein are known in the art as exemplified by Obrecht, D. and carbons may optionally be the point of attachment of the Villalgrodo, J. M., Solid-Supported Combinatorial and Par alkynyl Substituent. allel Synthesis of Small-Molecular-Weight Compound 0181. The terms “alkylamino” and “dialkylamino” refer to Libraries, Pergamon-Elsevier Science Limited (1998), and —NH(alkyl) and —NH(alkyl) radicals respectively. The include those such as the “split and pool” or “parallel syn term “aralkylamino” refers to a NH(aralkyl) radical. The thesis techniques, Solid-phase and solution-phase techniques, term alkylaminoalkyl refers to a (alkyl)NH-alkyl-radical; the and encoding techniques (see, for example, Czarnik, A. W., term dialkylaminoalkyl refers to a (alkyl)-N-alkyl-radical Curr. Opin. Chem. Bio. (1997) 1, 60. Thus, one embodiment The term “alkoxy' refers to an —O-alkyl radical. The term relates to a method of using the compounds described herein “mercapto” refers to an SH radical. The term “thioalkoxy” for generating derivatives or chemical libraries comprising: refers to an —S-alkyl radical. The term thioaryloxy refers to 1) providing a body comprising a plurality of wells; 2) pro an —S-aryl radical. viding one or more compounds identified by methods 0182. The term “aryl refers to a monocyclic, bicyclic, or described herein in each well; 3) providing an additional one tricyclic aromatic hydrocarbon ring system, wherein any ring or more chemicals in each well; 4) isolating the resulting one atom capable of Substitution can be substituted (e.g., by one or more products from each well. An alternate embodiment or more substituents). Examples of aryl moieties include, but relates to a method of using the compounds described herein are not limited to, phenyl, naphthyl, and anthracenyl. for generating derivatives or chemical libraries comprising: 0183 The term “cycloalkyl as employed herein includes 1) providing one or more compounds described herein cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydro attached to a solid Support; 2) treating the one or more com carbon groups having 3 to 12 carbons. Any Substitutable ring pounds identified by methods described herein attached to a atom can be substituted (e.g., by one or more Substituents). Solid Support with one or more additional chemicals; 3) iso The cycloalkyl groups can contain fused or spiro rings. Fused lating the resulting one or more products from the Solid Sup rings are rings that share a common carbon atom. Examples port. In the methods described above, “tags' or identifier or of cycloalkyl moieties include, but are not limited to, cyclo labeling moieties may be attached to and/or detached from propyl, cyclohexyl, methylcyclohexyl, adamantyl, and nor the compounds described herein or their derivatives, to facili bornyl. tate tracking, identification or isolation of the desired prod ucts or their intermediates. Such moieties are known in the 0.184 The terms "heterocyclyl or "heterocyclic group' art. The chemicals used in the aforementioned methods may refer to 3- to 14-membered non-aromatic ring structures (e.g., include, for example, Solvents, reagents, catalysts, protecting 3- to 14-membered rings, more preferably 3- to 7-membered group and deprotecting group reagents and the like. Examples rings), whose ring structures include one to four heteroatoms independently selected from O, N and S. The heterocyclyl or of Such chemicals are those that appear in the various syn heterocyclic groups can contain fused or spiro rings. Hetero thetic and protecting group chemistry texts and treatises ref cycles can also be polycycles, with each group having, e.g., erenced herein. 5-7 ring members. The term "heterocyclyl or "heterocyclic DEFINITIONS group' includes Saturated and partially saturated heterocyclyl structures. The term "heteroaryl refers to a 5-14 membered (0177. The term “halo” or “halogen” refers to any radical of (i.e., a 5-8 membered monocyclic, 8-12 membered bicyclic, fluorine, chlorine, bromine or iodine. or 11-14 membered tricyclic) aromatic ring system having (0178. The term “alkyl refers to a hydrocarbon chain that 1-3 ring heteroatoms if monocyclic, 1-6 ring heteroatoms if may be a straight chain or branched chain, containing the bicyclic, or 1-9 ring heteroatoms if tricyclic, said ring het indicated number of carbonatoms. For example, C-C alkyl eroatoms independently selected from O, N, and S (e.g., 1-3, indicates that the group may have from 1 to 12 (inclusive) 1-6, or 1-9 ring heteroatoms of N, O, or S if monocyclic, carbon atoms in it. The term “haloalkyl refers to an alkyl in bicyclic, or tricyclic, respectively). Any Substitutable ring which one or more hydrogenatoms are replaced by halo, and atom can be substituted (e.g., by one or more Substituents). includes alkyl moieties in which all hydrogens have been Heterocyclyl and heteroaryl groups include, for example, replaced by halo (e.g., perfluoroalkyl). The terms “arylalkyl thiophene, thianthrene, furan, pyran, isobenzofuran, US 2010/0331307 A1 Dec. 30, 2010 chromene, Xanthene, phenoxathiin, pyrrole, imidazole, pyra alkyl), cycloalkyl, haloalkyl (e.g., perfluoroalkyl Such as Zole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, CF), aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, pyridazine, indolizine, isoindole, indole, indazole, purine, alkenyl, alkynyl, cycloalkenyl, heterocycloalkenyl, alkoxy, quinolizine, isoquinoline, quinoline, phthalazine, naphthyri haloalkoxy (e.g., perfluoroalkoxy such as OCF), halo. dine, quinoxaline, quinazoline, cinnoline, pteridine, carba hydroxy, carboxy, carboxylate, cyano, nitro, amino, alkyl Zole, carboline, phenanthridine, acridine, pyrimidine, amino, SOH, sulfate, phosphate, methylenedioxy (—O— phenanthroline, phenazine, phenarsazine, phenothiazine, CH-O- wherein oxygens are attached to vicinal atoms), furazan, phenoxazine, pyrrolidine, oxolane, thiolane, ethylenedioxy, oxo (not a Substituent on heteroaryl), thioxo oxazole, piperidine, piperazine, morpholine, lactones, lac (e.g., C=S) (not a substituent on heteroaryl), imino (alkyl, tams such as aZetidinones and pyrrolidinones, Sultams, Sul aryl, aralkyl), S(O), alkyl (where n is 0-2), S(O), aryl (where tones, and the like. The heterocyclic or heteroaryl ring can be n is 0-2), S(O), heteroaryl (where n is 0-2), S(O), heterocy Substituted at one or more positions with Such Substituents as clyl (where n is 0-2), amine (mono-, di-, alkyl, cycloalkyl, described herein, as for example, halogen, alkyl, aralkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, Sulfhy thereof), ester (alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl), dryl, imino, amido, phosphate, phosphonate, phosphinate, amide (mono-, di-, alkyl, aralkyl, heteroaralkyl, aryl, het carbonyl, carboxyl, silyl ether, alkylthio. Sulfonyl, ketone, eroaryl, and combinations thereof), Sulfonamide (mono-, di-, aldehyde, ester, a heterocyclyl, anaromatic or heteroaromatic alkyl, aralkyl, heteroaralkyl, and combinations thereof). In moiety, —CF, —CN, or the like. one aspect, the Substituents on a group are independently any 0185. The term "heterocyclylalkyl, as used herein, refers one single, or any Subset of the aforementioned substituents. to an alkyl group Substituted with a heterocycle group. In another aspect, a substituent may itself be substituted with 0186 The term "cycloalkenyl refers to partially unsatur any one of the above substituents. ated, nonaromatic, monocyclic, bicyclic, or tricyclic hydro (0192. The term “selective' is meant at least 2-fold, 3-fold, carbon groups having 5 to 12 carbons, preferably 5 to 8 4-fold, 5-fold, 6-fold, or 10-fold greater modulation (e.g., carbons. The unsaturated carbon may optionally be the point activation) of PKM2 than PKM1. of attachment of the cycloalkenyl substituent. Any substitut 0193 The term “activator as used herein means an agent able ring atom can be substituted (e.g., by one or more Sub that (measurably) increases the activity of a pyruvate kinase stituents). The cycloalkenyl groups can contain fused or spiro (e.g., PKM2) or causes pyruvate kinase (e.g., PKM2) activity rings. Fused rings are rings that share a common carbonatom. to increase to a level that is greater than PKM2's basal levels Examples of cycloalkenyl moieties include, but are not lim of activity. For example, the activator may mimic the effect ited to, cyclohexenyl, cyclohexadienyl, or norbornenyl. caused by a natural ligand (e.g., FBP). The activator effect 0187. The term “heterocycloalkenyl refers to a partially caused by a compound provided herein may be to the same, or saturated, nonaromatic 5-10 membered monocyclic, 8-12 to a greater, or to a lesser extent than the activating effect membered bicyclic, or 11-14 membered tricyclic ring system caused by a natural ligand, but the same type of effect is having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if caused. A compound provided herein can be evaluated to bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms determine if it is an activator by measuring either directly or independently selected from O, N, and S (e.g., 1-3, 1-6, or 1-9 indirectly the activity of the pyruvate kinase when subjected ring heteroatoms of N, O, or S if monocyclic, bicyclic, or to said compound. The activity of a compound provided tricyclic, respectively). The unsaturated carbon or the het herein can be measured, for example, against a control Sub eroatom may optionally be the point of attachment of the stance. In some instances, the activity measured of the test heterocycloalkenyl Substituent. Any substitutable ring atom compound is for activation of PKM2. The activity of PKM2 can be substituted (e.g., by one or more substituents). The can be measured, for example, by monitoring the concentra heterocycloalkenyl groups can contain fused rings. Fused tion of a substrate such as ATP or NADH. rings are rings that share a common carbon atom. Examples (0194 The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms repre of heterocycloalkenyl include but are not limited to tetrahy sent methyl, ethyl, phenyl, trifluoromethanesulfonyl, non dropyridyl and dihydropyranyl. afluorobutanesulfonyl, p-toluenesulfonyl and methanesulfo 0188 The terms “hetaralkyl and "heteroaralkyl, as used nyl, respectively. A more comprehensive list of the herein, refers to an alkyl group substituted with a heteroaryl abbreviations utilized by organic chemists of ordinary skill in group. The ring heteroatoms of the compounds provided the art appears in the first issue of each volume of the Journal herein include N. O. S(O), and S(O). of Organic Chemistry; this list is typically presented in a table 0189 The term “oxo” refers to an oxygen atom, which entitled Standard List of Abbreviations. The abbreviations forms a carbonyl when attached to carbon, an N-oxide when contained in said list, and all abbreviations utilized by organic attached to nitrogen, and a sulfoxide or Sulfone when attached chemists of ordinary skill in the art are hereby incorporated by to sulfur. reference. (0190. The term “acyl” refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl, or Methods of Evaluating Compounds heteroarylcarbonyl substituent, any of which may be further 0.195 The compounds described herein can be evaluated Substituted (e.g., by one or more Substituents). for ability to modulate PKM2 (e.g., activate PKM2) by meth 0191 The term “substituents’ refers to a group “substi ods known in the art. In some embodiments, compounds tuted on an alkyl, cycloalkyl, alkenyl, alkynyl, heterocyclyl, described herein are evaluated for ability to modulate PKM2 heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl group at (e.g. activate PKM2) in serine deficient conditions. In some any Substitutable atom of that group. Any Substitutable atom embodiments, exemplary methods include contacting the can be substituted. Unless otherwise specified, such substitu compound with a cell-based assay which allows assessment ents include, without limitation, alkyl (e.g., C1, C2, C3, C4. of the ability to modulate (e.g., activate) PKM2. E.g., the C5, C6, C7, C8, C9, C10, C11, C12 straight or branched chain candidate compound can be contacted with a cell and mea US 2010/0331307 A1 Dec. 30, 2010
Suring the consumption of oxygen or production of lactate. A to the cell. This can allow an ACso (concentration at which change in cellular phosphoenolpyruvate, a change in glyc PKM2 is activated 50%) value to be derived. The total fold erol-phosphate, a change in ribose or deoxyribose, a change increase in activity over mock-treated cells can also be cal in lipid synthesis, or a change in glucose conversion to lipid or culated, and the "maximum level of activation' can be used to nucleic acids or amino acids or protein can also be used to distinguish between compounds that fully activate PKM2 and evaluate a compound for its ability to modulate PKM2 (e.g., compounds that can only partially activate PKM2. In the case activate PKM2). The evaluation could also include measuring of measuring PKM2 activity from tissue (for example, in a a change in pyruvate or a determination of an alteration in cell tumor), animals harboring the tissue? tumor of interest can mitochondrial membrane potential, e.g., as measured by fluo be dosed with a compound. After a specified period of time in rescent potentiometric dyes. which exposure has been achieved in the target tissue? tumor (0196. The activity of the PKM enzyme measured in the of interest, the tissue? tumor can then be harvested from the screening/testing assay may be measured by, e.g., monitoring animal, Snap-frozen, and then lysed and homogenized. The the concentration of a substrate (e.g., ATP or NADH) present amount of pyruvate kinase activity in this lysate can then be in the reaction mixture. Pyruvate, produced by the enzymatic quantitated as described above. activity of pyruvate kinase, is converted into lactate by lactate (0199 PKM1 and PKM2 for use in the screening/testing dehydrogenase, which requires the consumption of NADH methods described herein may be produced by any method (NADH->NAD+). Thus, the activity of PKM2 can be indi known in the art for expression of recombinant proteins. For rectly measured by monitoring the consumption of NADH example, nucleic acids that encode the desired polypeptide through, e.g., fluorescence assays. Additionally, the activity may be introduced into various cell types or cell-free systems of the PKM2 enzyme can be directly monitored by measuring for expression. Eukaryotic (e.g., COS, HEK293T. CHO, and the production of ATP, as ATP is produced when phospho NIH cell lines) and prokaryotic (e.g., E. coli) expression enolpyruvate is converted to pyruvate. Methods for monitor systems may be generated in which a PKM sequence is intro ing the amount of substrate in a reaction mixture include, e.g., duced into a plasmid or other vector, which is then used to absorbance, fluorescence, Raman scattering, phosphores transform living cells. Constructs in which the PKM cDNA cence, luminescence, luciferase assays, and radioactivity. contains the entire open reading frame, or biologically active 0197) The screening procedure requires the presence of fragment thereof, are inserted in the correct orientation into specific components in the reaction mixture. Components an expression plasmid and may be used for protein expres utilized in the assay include, e.g., a nucleoside diphosphate Sion. Prokaryotic and eukaryotic expression systems allow (e.g., ADP), phosphoenolpyruvate, NADH, lactate dehydro for the expression and recovery of fusion proteins in which genase, FBP, a reducing agent (e.g., dithiothreitol), a deter the PKM protein is covalently linked to a tag molecule on gent (e.g., Brij 35), glycerol, and a solvent (e.g., DMSO). either the amino terminal or carboxy terminal side, which Exemplary reaction conditions are found in Table 1. facilitates identification and/or purification. Examples of tags that can be used include hexahistidine, HA, FLAG, and c-myc TABLE 1. epitope tags. An enzymatic or chemical cleavage site can be Amount in engineered between the PKM protein and the tag molecule so Activation that the tag can be removed following purification. Component of Reaction Condition Assay 0200 Compounds useful as PKM2 activators are those ADP O.1-5.0 mM demonstrate specificity and activation of PKM2 enzyme in Phosphoenolpyruvate O.1-5.0 mM the absence of FBP to a level greater than that of 10, 15, 20, NADH 10-1000 M 25, 30,35, 40, 45, 50,55, 60, 65,70, 75, 80, 85,90, 95, 99, or Lactate dehydrogenase 0.1-10 units Fructose-1,6-bisphosphate O 100% in the presence of FBP. Furthermore, compounds can DTT O. 1-50 nM be evaluated in the presence or absence of a phosphotyrosine Brij 35 O.O1-1% peptide. Phosphotyrosine peptide binding to PKM2 leads to a Glycerol O.1-10% dissociation of FBP from PKM2 and conformational changes Pyruvate Kinase M2 (used for screen) 1-100 pg of PKM2 from an active, tetrameric form to an inactive form. DMSO 1-10% Compounds that bind to PKM2 and lock the enzyme in the active confirmation even in the presence of a phosphotyrosine 0198 In some embodiments, a compound such as a com peptide will lead to the loss of allosteric control of PKM2 pound described herein, can be evaluated in a cellular/ex vivo needed for shunting the biochemical intermediates from gly assay. For example, a cell is treated with a compound colysis into biosynthesis of other intermediates. This, in turn, described herein (i.e., a PKM2 activator), and the compound will lead to inhibition of growth of cancer cells, activated is evaluated, for example for its ability to enter the cell and immune cells and fat cells. bind to PKM2, inducing an activated conformation of PKM2. The excess unbound compound can then be washed away Methods of Treatment with PBS, and the cells lysed, for example, by snap-freezing on dry ice, followed by addition of a detergent-containing 0201 In one embodiment, provided is a method for treat lysis buffer. The lysate, in which activated PKM2 remains ing or preventing a disease, condition or disorder as described intact, can then be removed and added to a chemical cocktail herein (e.g., treating) comprising administering a compound, including the chemicals necessary to measure pyruvate a pharmaceutically acceptable salt of a compound orpharma kinase activity. The assay can be coupled to another assay ceutical composition comprising a compound described Such as an assay that is coupled to the LDHa enzyme. The herein (e.g., a compound of formula (I), (I-a), (II) or in FIG. amount of pyruvate kinase activity that is measured can then 1). be normalized to the total protein content in the lysate, and 0202 The compounds and compositions described herein related to the concentration of PKM2 activator that was added can be administered to cells in culture, e.g. in vitro or ex vivo, US 2010/0331307 A1 Dec. 30, 2010 or to a subject, e.g., in vivo, to treat, prevent, and/or diagnose 0209. Other exemplary cancers include: Acute Lympho a variety of disorders, including those described herein below. blastic Leukemia, Adult; Acute Lymphoblastic Leukemia, 0203 As used herein, the term “treat' or “treatment is Childhood; Acute Myeloid Leukemia, Adult; Adrenocortical defined as the application or administration of a compound, Carcinoma; Adrenocortical Carcinoma, Childhood; AIDS alone or in combination with, a second compound to a Sub Related Lymphoma; AIDS-Related Malignancies; Anal Can ject, e.g., a patient, or application or administration of the cer; Astrocytoma, Childhood Cerebellar; Astrocytoma, compound to an isolated tissue or cell, e.g., cell line, from a Childhood Cerebral; Bile Duct Cancer, Extrahepatic; Bladder Subject, e.g., a patient, who has a disorder (e.g., a disorder as Cancer; Bladder Cancer, Childhood; Bone Cancer, Osteosa described herein), a symptom of a disorder, or a predisposi rcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma, tion toward a disorder, with the purpose to cure, heal, allevi ate, relieve, alter, remedy, ameliorate, improve or affect the Childhood; Brain Tumor, Adult; Brain Tumor, Brain Stem disorder, one or more symptoms of the disorder or the pre Glioma, Childhood; Brain Tumor, Cerebellar Astrocytoma, disposition toward the disorder (e.g., to prevent at least one Childhood; Brain Tumor, Cerebral Astrocytoma/Malignant symptom of the disorder or to delay onset of at least one Glioma, Childhood; Brain Tumor, Ependymoma, Childhood; symptom of the disorder). Brain Tumor, Medulloblastoma, Childhood; Brain Tumor, 0204 As used herein, an amount of a compound effective Supratentorial Primitive Neuroectodermal Tumors, Child to treat a disorder, or a “therapeutically effective amount hood; Brain Tumor, Visual Pathway and Hypothalamic refers to an amount of the compound which is effective, upon Glioma, Childhood; Brain Tumor, Childhood (Other); Breast single or multiple dose administration to a subject, in treating Cancer; Breast Cancer and Pregnancy; Breast Cancer, Child a cell, or in curing, alleviating, relieving or improving a hood; Breast Cancer, Male; Bronchial Adenomas/Carcinoids, subject with a disorder beyond that expected in the absence of Childhood; Carcinoid Tumor, Childhood; Carcinoid Tumor, Such treatment. Gastrointestinal; Carcinoma, Adrenocortical; Carcinoma, 0205 As used herein, an amount of a compound effective Islet Cell: Carcinoma of Unknown Primaiy; Central Nervous to prevent a disorder, or a “a prophylactically effective System Lymphoma, Primary: Cerebellar Astrocytoma, amount of the compound refers to an amount effective, upon Childhood; Cerebral Astrocytoma/Malignant Glioma, Child single- or multiple-dose administration to the Subject, in pre hood; Cervical Cancer; Childhood Cancers; Chronic Lym venting or delaying the occurrence of the onset or recurrence phocytic Leukemia; Chronic Myelogenous Leukemia; of a disorder or a symptom of the disorder. Chronic Myeloproliferative Disorders; Clear Cell Sarcoma of 0206. As used herein, the term "subject” is intended to Tendon Sheaths; Colon Cancer, Colorectal Cancer, Child include human and non-human animals. Exemplary human hood; Cutaneous T-Cell Lymphoma; Endometrial Cancer; Subjects include a human patient having a disorder, e.g., a Ependymoma, Childhood: Epithelial Cancer, Ovarian; disorder described herein or a normal subject. The term “non Esophageal Cancer, Esophageal Cancer, Childhood; Ewing's human animals' includes all vertebrates, e.g., non-mammals Family of Tumors; Extracranial Germ Cell Tumor, Child (such as chickens, amphibians, reptiles) and mammals, such hood; Extragonadal Germ Cell Tumor; Extrahepatic Bile as non-human primates, domesticated and/or agriculturally Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Can useful animals, e.g., sheep, dog, cat, cow, pig, etc. cer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastric (Stomach) Cancer, Childhood; Gastrointes Neoplastic Disorders tinal Carcinoid Tumor; Germ. Cell Tumor, Extracranial, Childhood; Germ Cell Tumor, Extragonadal; Germ Cell 0207. A compound or composition described herein can Tumor, Ovarian: Gestational Trophoblastic Tumor; Glioma, be used to treat a neoplastic disorder. A “neoplastic disorder Childhood Brain Stem; Glioma, Childhood Visual Pathway is a disease or disorder characterized by cells that have the and Hypothalamic: Hairy Cell Leukemia; Head and Neck capacity for autonomous growth or replication, e.g., an abnor Cancer; Hepatocellular (Liver) Cancer. Adult (Primary); mal state or condition characterized by proliferative cell Hepatocellular (Liver) Cancer, Childhood (Primary); growth. Exemplary neoplastic disorders include: carcinoma, Hodgkin's Lymphoma, Adult; Hodgkin's Lymphoma, Child sarcoma, metastatic disorders (e.g., tumors arising from pros hood; Hodgkin's Lymphoma During Pregnancy; Hypopha tate, colon, lung, breast and liver origin), hematopoietic neo ryngeal Cancer, Hypothalamic and Visual Pathway Glioma, plastic disorders, e.g., leukemias, metastatic tumors. Preva Childhood; Intraocular Melanoma; Islet Cell Carcinoma (En lent cancers include: breast, prostate, colon, lung, liver, and docrine Pancreas); Kaposi's Sarcoma; Kidney Cancer, pancreatic cancers. Treatment with the compound may be in Laryngeal Cancer, Laryngeal Cancer, Childhood; Leukemia, an amount effective to ameliorate at least one symptom of the Acute Lymphoblastic, Adult, Leukemia, Acute Lymphoblas neoplastic disorder, e.g., reduced cell proliferation, reduced tic, Childhood; Leukemia, Acute Myeloid, Adult; Leukemia, tumor mass, etc. Acute Myeloid, Childhood; Leukemia, Chronic Lympho 0208. The disclosed methods are useful in the prevention cytic, Leukemia, Chronic Myelogenous; Leukemia, Hairy and treatment of cancer, including for example, Solid tumors, Cell: Lip and Oral Cavity Cancer; Liver Cancer, Adult (Pri Soft tissue tumors, and metastases thereof. The disclosed mary): Liver Cancer, Childhood (Primary); Lung Cancer, methods are also useful in treating non-Solid cancers. Exem Non-Small Cell: Lung Cancer, Small Cell; Lymphoblastic plary Solid tumors include malignancies (e.g., Sarcomas, Leukemia, Adult Acute; Lymphoblastic Leukemia, Child adenocarcinomas, and carcinomas) of the various organ sys hood Acute; Lymphocytic Leukemia, Chronic; Lymphoma, tems. Such as those of lung, breast, lymphoid, gastrointestinal AIDS-Related; Lymphoma, Central Nervous System (Pri (e.g., colon), and genitourinary (e.g., renal, urothelial, or tes mary); Lymphoma, Cutaneous T-Cell; Lymphoma, ticular tumors) tracts, pharynx, prostate, and ovary. Exem Hodgkin’s, Adult, Lymphoma, Hodgkin's, Childhood; Lym plary adenocarcinomas include colorectal cancers, renal-cell phoma, Hodgkin's During Pregnancy; Lymphoma, Non carcinoma, liver cancer, non-Small cell carcinoma of the lung, Hodgkin’s, Adult; Lymphoma, Non-Hodgkin’s, Childhood; and cancer of the Small intestine. Lymphoma, Non-Hodgkin's During Pregnancy; Lymphoma, US 2010/0331307 A1 Dec. 30, 2010
Primary Central Nervous System; Macroglobulinemia, therapies, immunotherapy, and hormonal therapy. Examples Waldenstrom's; Male Breast Cancer; Malignant Mesothe of each of these treatments are provided below. lioma, Adult; Malignant Mesothelioma, Childhood; Malig 0212 Chemotherapy nant Thymoma; Medulloblastoma, Childhood; Melanoma; 0213. In some embodiments, a compound described Melanoma, Intraocular, Merkel Cell Carcinoma; Mesothe herein is administered with one or more chemotherapies. lioma, Malignant; Metastatic Squamous Neck Cancer with Chemotherapy is the treatment of cancer with drugs that can Occult Primary: Multiple Endocrine Neoplasia Syndrome, destroy cancer cells. “Chemotherapy' usually refers to cyto Childhood; Multiple Myeloma/Plasma Cell Neoplasm; toxic drugs which affect rapidly dividing cells in general, in Mycosis Fungoides; Myelodysplastic Syndromes: Myelog contrast with targeted therapy. Chemotherapy drugs interfere enous Leukemia, Chronic; Myeloid Leukemia, Childhood with cell division in various possible ways, e.g., with the Acute; Myeloma, Multiple; Myeloproliferative Disorders, duplication of DNA or the separation of newly formed chro mosomes. Most forms of chemotherapy target all rapidly Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopha dividing cells and are not specific for cancer cells, although ryngeal Cancer; Nasopharyngeal Cancer, Childhood; Neuro Some degree of specificity may come from the inability of blastoma; Non-Hodgkin's Lymphoma, Adult: Non many cancer cells to repair DNA damage, while normal cells Hodgkin's Lymphoma, Childhood; Non-Hodgkin’s generally can. Lymphoma During Pregnancy. Non-Small Cell Lung Can 0214 Examples of chemotherapeutic agents used in can cer; Oral Cancer, Childhood; Oral Cavity and Lip Cancer; cer therapy include, for example, antimetabolites (e.g., folic Oropharyngeal Cancer, Osteosarcoma/Malignant Fibrous acid, purine, and pyrimidine derivatives) and alkylating Histiocytoma of Bone: Ovarian Cancer, Childhood: Ovarian agents (e.g., nitrogen mustards, nitrosoureas, platinum, alkyl Epithelial Cancer: Ovarian Germ Cell Tumor: Ovarian Low Sulfonates, hydrazines, triaZenes, aziridines, spindle poison, Malignant Potential Tumor; Pancreatic Cancer; Pancreatic cytotoxic agents, toposimerase inhibitors and others). Exem Cancer, Childhood; Pancreatic Cancer, Islet Cell; Paranasal plary agents include Aclarubicin, Actinomycin, Alitretinon, Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin, Cancer; Pheochromocytoma; Pineal and Supratentorial Amsacrine, Anagrelide, Arsenic trioxide, Asparaginase, Primitive Neuroectodermal Tumors, Childhood; Pituitary Atrasentan, Belotecan, Bexarotene, endamustine, Bleomy Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleurop cin, Bortezomib, Busulfan, Camptothecin, Capecitabine, ulmonary Blastoma; Pregnancy and Breast Cancer, Preg Carboplatin, Carboquone, Carmofur, Carmustine, Celecoxib, nancy and Hodgkin's Lymphoma; Pregnancy and Non Chlorambucil, Chlormethine, Cisplatin, Cladribine, Clofara Hodgkin's Lymphoma; Primary Central Nervous System bine, Crisantaspase, Cyclophosphamide, Cytarabine, Dacar Lymphoma; Primary Liver Cancer, Adult; Primary Liver bazine, Dactinomycin, Daunorubicin, Decitabine, Demecol Cancer, Childhood; Prostate Cancer; Rectal Cancer, Renal cine, Docetaxel, Doxorubicin, Efaproxiral, Elesclomol, Cell (Kidney) Cancer; Renal Cell Cancer, Childhood; Renal Elsamitrucin, Enocitabine, Epirubicin, Estramustine, Etoglu Pelvis and Ureter, Transitional Cell Cancer; Retinoblastoma; cid, Etoposide, Floxuridine, Fludarabine, Fluorouracil Rhabdomyosarcoma, Childhood; Salivary Gland Cancer; (5FU), Fotemustine, Gemcitabine, Gliadel implants, Salivary Gland Cancer, Childhood; Sarcoma, Ewing's Fam Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, ily of Tumors; Sarcoma, Kaposi's; Sarcoma (Osteosarcoma)/ Irinotecan, Irofulven, IXabepilone, Larotaxel, Leucovorin, Malignant Fibrous Histiocytoma of Bone: Sarcoma, Rhab Liposomal doxorubicin, Liposomal daunorubicin, domyosarcoma, Childhood; Sarcoma, Soft Tissue. Adult; Lonidamine, Lomustine, Lucanthone, Mannosulfan, Maso Sarcoma, Soft Tissue, Childhood: Sezary Syndrome: Skin procol, Melphalan, Mercaptopurine, Mesna, Methotrexate, Cancer; Skin Cancer, Childhood; Skin Cancer (Melanoma); Methyl aminolevulinate, Mitobronitol, MitoguaZone, Mito Skin Carcinoma, Merkel Cell: Small Cell Lung Cancer; tane, Mitomycin, Mitoxantrone, Nedaplatin, Nimustine, Small Intestine Cancer, Soft Tissue Sarcoma, Adult; Soft Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin, Paclitaxel, Tissue Sarcoma, Childhood: Squamous Neck Cancer with Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin, Pix Occult Primary, Metastatic; Stomach (Gastric) Cancer; antrone, Plicamycin, Porfimer sodium, Prednimustine, Pro Stomach (Gastric) Cancer, Childhood; Supratentorial Primi carbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitab tive Neuroectodermal Tumors, Childhood; T-Cell Lym ine, Semustine, Sitimagene ceradenovec, Satraplatin, phoma, Cutaneous; Testicular Cancer; Thymoma, Child Streptozocin, Talaporfin, Tegafur-uracil, Temoporfin, Temo hood; Thymoma, Malignant; Thyroid Cancer; Thyroid Zolomide, Teniposide, Tesetaxel, Testolactone, Tetranitrate, Cancer, Childhood; Transitional Cell Cancer of the Renal Thiotepa, Tiazofurin, Tioguanine, Tipifarnib, Topotecan, Pelvis and Ureter; Trophoblastic Tumor, Gestational; Trabectedin, Triaziquone, Triethylenemelamine, Triplatin, Unknown Primary Site, Cancer of Childhood; Unusual Can Tretinoin, Treosulfan, Trofosfamide, Uramustine, Valrubicin, cers of Childhood; Ureter and Renal Pelvis, Transitional Cell Verteporfin, Vinblastine, Vincristine, Vindesine, Vinflunine, Cancer; Urethral Cancer; Uterine Sarcoma; Vaginal Cancer; Vinorelbine, Vorinostat, Zorubicin, and other cytostatic or Visual Pathway and Hypothalamic Glioma, Childhood; Vul cytotoxic agents described herein. var Cancer; Waldenstrom's Macro globulinemia; and Wilms 0215 Because some drugs work better together than Tumor. Metastases of the aforementioned cancers can also be alone, two or more drugs are often given at the same time. treated or prevented in accordance with the methods Often, two or more chemotherapy agents are used as combi described herein. nation chemotherapy. In some embodiments, the chemo 0210 Cancer Combination Therapies therapy agents (including combination chemotherapy) can be 0211. In some embodiments, a compound described used in combination with a compound described herein. herein is administered together with one or more additional 0216 Targeted Therapy cancer treatments. Exemplary cancer treatments include, for 0217. In some embodiments, a compound described example: chemotherapy, targeted therapies such as antibody herein is administered with one or more targeted therapies. US 2010/0331307 A1 Dec. 30, 2010
Targeted therapy constitutes the use of agents specific for the or prevent an over-weight condition. “Over-weight” refers to deregulated proteins of cancer cells. Small molecule targeted a condition in which a subject has a body mass index of therapy drugs are generally inhibitors of enzymatic domains greater or equal to 25.0. The body mass index (BMI) and other on mutated, overexpressed, or otherwise critical proteins definitions are according to the “NIH Clinical Guidelines on within the cancer cell. Prominent examples are the tyrosine the Identification and Evaluation, and Treatment of Over kinase inhibitors such as Axitinib, Bosutinib, Cediranib, weight and Obesity in Adults” (1998). Treatment with the dasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaur compound may be in an amount effective to alter the weight tinib, Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Van of the subject, e.g., by at least 2, 5, 7, 10, 12, 15, 20, 25, 30, 25, detanib, and also cyclin-dependent kinase inhibitors such as 40, 45, 50, or 55%. Treatment with a compound may be in an Alvocidib and Seliciclib. Monoclonal antibody therapy is amount effective to reduce the body mass index of the subject, another strategy in which the therapeutic agent is an antibody e.g., to less than 30, 28, 27, 25, 22, 20, or 18. The compounds which specifically binds to a protein on the surface of the can be used to treat or prevent aberrant or inappropriate cancer cells. Examples include the anti-HER2/neu antibody weight gain, metabolic rate, or fat deposition, e.g., anorexia, trastuzumab (HERCEPTINR) typically used in breast can bulimia, obesity, diabetes, or hyperlipidemia (e.g., elevated cer, and the anti-CD20 antibody rituximab and Tositumomab triglycerides and/or elevated cholesterol), as well as disorders typically used in a variety of B-cell malignancies. Other offat or lipid metabolism. exemplary anbibodies include Cetuximab, Panitumumab, 0225. A compound or composition described herein can Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, be administered to treat obesity associated with Prader-Willi and Gemtuzumab. Exemplary fusion proteins include Syndrome (PWS). PWS is a genetic disorder associated with Aflibercept and Denileukin diftitox. In some embodiments, obesity (e.g., morbid obesity). the targeted therapy can be used in combination with a com 0226. A compound or composition described herein can pound described herein. be used to reduce body fat, prevent increased body fat, reduce 0218. Targeted therapy can also involve small peptides as cholesterol (e.g., total cholesterol and/or ratios of total cho “homing devices” which can bind to cell surface receptors or lesterol to HDL cholesterol), and/or reduce appetite in indi affected extracellular matrix surrounding the tumor. Radio viduals having PWS associated obesity, and/or reduce comor nuclides which are attached to these peptides (e.g., RGDs) bidities such as diabetes, cardiovascular disease, and stroke. eventually kill the cancer cell if the nuclide decays in the vicinity of the cell. An example of such therapy includes Compositions and Routes of Administration BEXXARCR). 0227. The compositions delineated herein include the 0219. Immunotherapy compounds delineated herein (e.g., a compound described 0220. In some embodiments, a compound described herein), as well as additional therapeutic agents if present, in herein is administered with one or more immunotherapies. amounts effective for achieving a modulation of disease or Cancer immunotherapy refers to a diverse set of therapeutic disease symptoms, including those described herein. strategies designed to induce the patient's own immune sys 0228. The term “pharmaceutically acceptable carrier or tem to fight the tumor. Contemporary methods for generating adjuvant” refers to a carrier or adjuvant that may be admin an immune response against tumors include intravesicular istered to a patient, together with a compound provided here BCG immunotherapy for superficial bladder cancer, and use with, and which does not destroy the pharmacological activ of interferons and other cytokines to induce an immune ity thereof and is nontoxic when administered in doses response in renal cell carcinoma and melanoma patients. Sufficient to deliver a therapeutic amount of the compound. 0221 Allogeneic hematopoietic stem cell transplantation 0229. Pharmaceutically acceptable carriers, adjuvants and can be considered a form of immunotherapy, since the vehicles that may be used in the pharmaceutical compositions donor's immune cells will often attack the tumor in a graft provided herewith include, but are not limited to, ion Versus-tumor effect. In some embodiments, the immuno exchangers, alumina, aluminum Stearate, lecithin, self-emul therapy agents can be used in combination with a compound sifying drug delivery systems (SEDDS) such as d-C.-toco described herein. pherol polyethyleneglycol 1000 succinate, surfactants used in 0222 Hormonal Therapy pharmaceutical dosage forms such as Tweens or other similar 0223) In some embodiments, a compound described polymeric delivery matrices, serum proteins. Such as human herein is administered with one or more hormonal therapies. serum albumin, buffer Substances such as phosphates, gly The growth of some cancers can be inhibited by providing or cine, Sorbic acid, potassium Sorbate, partial glyceride mix blocking certain hormones. Common examples of hormone tures of Saturated vegetable fatty acids, water, salts or elec sensitive tumors include certain types of breast and prostate trolytes, such as protamine Sulfate, disodium hydrogen cancers. Removing or blocking estrogen or testosterone is phosphate, potassium hydrogen phosphate, Sodium chloride, often an important additional treatment. In certain cancers, Zinc salts, colloidal silica, magnesium trisilicate, polyvinyl administration of hormone agonists, such as progestogens pyrrolidone, cellulose-based Substances, polyethylene gly may be therapeutically beneficial. In some embodiments, the col, Sodium carboxymethylcellulose, polyacrylates, waxes, hormonal therapy agents can be used in combination with a polyethylene-polyoxypropylene-block polymers, polyethyl compound described herein. ene glycol and wool fat. Cyclodextrins such as C.-, 3-, and Y-cyclodextrin, or chemically modified derivatives such as Obesity and Fat Disorders hydroxyalkylcyclodextrins, including 2- and 3-hydroxypro 0224. A compound or composition described herein can pyl-f-cyclodextrins, or other solubilized derivatives may also be used to treat or prevent obesity, e.g., in a human Subject, be advantageously used to enhance delivery of compounds of e.g. a child or adult subject. “Obesity” refers to a condition in the formulae described herein. which a subject has a body mass index of greater than or equal 0230. The pharmaceutical compositions provided here to 30. Many compounds described herein can be used to treat with may be administered orally, parenterally, by inhalation US 2010/0331307 A1 Dec. 30, 2010
spray, topically, rectally, nasally, buccally, vaginally or via an release the active components. Such materials include, but are implanted reservoir, preferably by oral administration or not limited to, cocoa butter, beeswax and polyethylene gly administration by injection. The pharmaceutical composi cols. tions provided herewith may contain any conventional non 0234 Topical administration of the pharmaceutical com toxic pharmaceutically-acceptable carriers, adjuvants or positions provided herewith is useful when the desired treat vehicles. In some cases, the pH of the formulation may be ment involves areas or organs readily accessible by topical adjusted with pharmaceutically acceptable acids, bases or application. For application topically to the skin, the pharma buffers to enhance the stability of the formulated compound ceutical composition should be formulated with a suitable or its delivery form. The term parenteral as used herein ointment containing the active components Suspended or dis includes Subcutaneous, intracutaneous, intravenous, intra solved in a carrier. Carriers for topical administration of the muscular, intraarticular, intraarterial, intrasynovial, intraster compounds provided herewith include, but are not limited to, nal, intrathecal, intralesional and intracranial injection or mineral oil, liquid petroleum, white petroleum, propylene infusion techniques. glycol, polyoxyethylene polyoxypropylene compound, 0231. The pharmaceutical compositions may be in the emulsifying wax and water. Alternatively, the pharmaceutical form of a sterile injectable preparation, for example, as a composition can beformulated with a suitable lotion or cream sterile injectable aqueous or oleaginous Suspension. This sus containing the active compound Suspended or dissolved in a pension may beformulated according to techniques known in carrier with Suitable emulsifying agents. Suitable carriers the art using Suitable dispersing or wetting agents (such as, for include, but are not limited to, mineral oil, sorbitan example, Tween 80) and Suspending agents. The sterile monostearate, polysorbate 60, cetyl esters wax, cetearyl alco injectable preparation may also be a sterile injectable solution hol, 2-octyldodecanol, benzyl alcohol and water. The phar or Suspension in a non-toxic parenterally acceptable diluent maceutical compositions provided herewith may also be topi or solvent, for example, as a solution in 1,3-butanediol. cally applied to the lower intestinal tract by rectal Suppository Among the acceptable vehicles and solvents that may be formulation or in a suitable enema formulation. Topically employed are mannitol, water, Ringer's solution and isotonic transdermal patches are also included. sodium chloride solution. In addition, sterile, fixed oils are 0235. The pharmaceutical compositions provided here conventionally employed as a solventor Suspending medium. with may be administered by nasal aerosol or inhalation. Such For this purpose, any bland fixed oil may be employed includ compositions are prepared according to techniques well ing synthetic mono- or diglycerides. Fatty acids, such as oleic known in the art of pharmaceutical formulation and may be acid and its glyceride derivatives are useful in the preparation prepared as Solutions in saline, employing benzyl alcohol or of injectables, as are natural pharmaceutically-acceptable other Suitable preservatives, absorption promoters to enhance oils, such as olive oil or castor oil, especially in their poly bioavailability, fluorocarbons, and/or other solubilizing or oxyethylated versions. These oil solutions or Suspensions dispersing agents known in the art. may also contain a long-chain alcohol diluent or dispersant, 0236 When the compositions provided herewith com prise a combination of a compound of the formulae described or carboxymethyl cellulose or similar dispersing agents herein and one or more additional therapeutic or prophylactic which are commonly used in the formulation of pharmaceu agents, both the compound and the additional agent should be tically acceptable dosage forms such as emulsions and or present at dosage levels of between about 1 to 100%, and Suspensions. Other commonly used Surfactants such as more preferably between about 5 to 95% of the dosage nor Tweens or Spans and/or other similar emulsifying agents or mally administered in a monotherapy regimen. The addi bioavailability enhancers which are commonly used in the tional agents may be administered separately, as part of a manufacture of pharmaceutically acceptable solid, liquid, or multiple dose regimen, from the compounds provided here other dosage forms may also be used for the purposes of with. Alternatively, those agents may be part of a single dos formulation. age form, mixed together with the compounds provided here 0232. The pharmaceutical compositions provided here with in a single composition. with may be orally administered in any orally acceptable 0237. The compounds described herein can, for example, dosage form including, but not limited to, capsules, tablets, be administered by injection, intravenously, intraarterially, emulsions and aqueous Suspensions, dispersions and solu Subdermally, intraperitoneally, intramuscularly, or Subcuta tions. In the case of tablets for oral use, carriers which are neously; or orally, buccally, nasally, transmucosally, topi commonly used include lactose and corn starch. Lubricating cally, in an ophthalmic preparation, or by inhalation, with a agents, such as magnesium Stearate, are also typically added. dosage ranging from about 0.5 to about 100 mg/kg of body For oral administration in a capsule form, useful diluents weight, alternatively dosages between 1 mg and 1000 include lactose and dried corn starch. When aqueous Suspen mg/dose, every 4 to 120 hours, or according to the require sions and/or emulsions are administered orally, the active ments of the particular drug. The methods herein contemplate ingredient may be suspended or dissolved in an oily phase is administration of an effective amount of compound or com combined with emulsifying and/or Suspending agents. If pound composition to achieve the desired or stated effect. desired, certain Sweetening and/or flavoring and/or coloring Typically, the pharmaceutical compositions provided here agents may be added. with will be administered from about 1 to about 6 times per 0233. The pharmaceutical compositions provided here day or alternatively, as a continuous infusion. Such adminis with may also be administered in the form of suppositories for tration can be used as a chronic or acute therapy. The amount rectal administration. These compositions can be prepared by of active ingredient that may be combined with the carrier mixing a compound provided herewith a suitable non-irritat materials to produce a single dosage form will vary depend ing excipient which is solid at room temperature but liquid at ing upon the host treated and the particular mode of admin the rectal temperature and therefore will melt in the rectum to istration. A typical preparation will contain from about 5% to US 2010/0331307 A1 Dec. 30, 2010
about 95% active compound (w/w). Alternatively, such Reaction Buffer: 100 mM KC1, 50 mM Tris pH 7.5, 5 mM preparations contain from about 20% to about 80% active MgCl2, 1 mM DTT, 0.03% BSA. compound. 0238 Lower or higher doses than those recited above may Example 2 be required. Specific dosage and treatment regimens for any Compounds and Their Preparation particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the 0248 age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the Scheme 2: patient's disposition to the disease, condition or symptoms, OH OEt and the judgment of the treating physician. 0239 Upon improvement of a patient's condition, a main CHSI, KCO CISOH tenance dose of a compound, composition or combination -e- provided herewith may be administered, if necessary. Subse DMF, rt, -10°C., 10 mins quently, the dosage or frequency of administration, or both, Overnight may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms Br Br have been alleviated to the desired level. Patients may, how 1 ever, require intermittent treatment on a long-term basis upon OEt any recurrence of disease symptoms. SOCI in-()-cool -e- Patient Selection and Monitoring Pyridine, DCM, 12 h. 0240. The compounds described herein can modulate rt PKM2. Accordingly, a patient and/or subject can be selected for treatment using a compound described herein by first Br evaluating the patient and/or subject to determine whether the 2 COOEt subject is in need of modulation of PKM2, and if the subject OEt is determined to be in need of modulation of PKM2, then O administering to the Subject a compound described herein. S n N 0241. A subject can be evaluated as being in need of modu H LiOH lation of PKM2 using methods known in the art, e.g., by THF-HO measuring the presence and/or activity of PKM2 in the patient. In some embodiments, the activity and/or level of reflux, 12hrs PKM2 is evaluated in the cancer. Br 0242 A patient receiving a compound described herein 3 can be monitored, for example, for improvement in the con MeO dition and/or adverse effects. Improvement of a patient's con COOH M N dition can be evaluated, for example, by monitoring the OEt HN N growth, absence of growth, or regression of the cancer (e.g., a O \ / S n tumor). In some embodiments, the patient is evaluated using N (6) a radiological assay or evaluation of hemolytic parameters. H -- EDCL, HOBt, EXAMPLES DIPEA, DMF, 12 h, rt Example 1 Br 4 PKM2 Assay O Procedure: 1no R A” S a. w 0243 PKM2 stock enzyme solution was diluted in N C-N N Reaction Buffer | V / 0244 2 LL of compound was added into each well first, O and then 180 uL of the Reaction Mix was added. 0245 Reaction mixture with compound (without ADP) Br were incubated for 30 minutes at 4°C. 7 0246 Plates were re-equilibrated to room temperature Compound 6: prior to adding 20 LL ADP to initiate the reaction. 0247 Reaction progress was measured as changes in absorbance at 340 nm wavelength at room temperature BINAP, Pd(OAc) (25° C) BocN NH + Br -e- Reaction Mix: PKM2 (50 ng/well), ADP (0.7 mM), PEP Cs2CO3, 1,4-dioxane (0.15 mM), NADH (180 uM), LDH (2 units) in Reaction 80°C., 12 hrs Buffer US 2010/0331307 A1 Dec. 30, 2010 18
acetate. The aqueous layer was acidified with citric acid -continued (pH-4) and extracted again with ethyl acetate (2x25 mL). The MeO combined organic layer was dried over Na2SO4 and concen trated under reduced pressure. The resultant acid was further A w ether? HC BocN N -e- washed with hexane to get pure compound 4 (0.500 g, 89%). rt, 2h 0254 MS (400.24)397.9 (M-2 peak, negative mode); H NMR (200 MHz, DMSO-d) 1.20 (t, 3H), 4.18 (q, 2H), 7.10 5 (d. 1H), 7.10-7.20 (d. 3H), 7.60-8.0 (m, 4H), 10.6 (s, 1H), MeO 12.6 (bs, 1H). 0255 General procedure for Compound 7: To a solution of CHOHN N 4-(5-bromo-2-ethoxyphenylsulfonamido)benzoic acid (com pound 4, 0.300 g, 0.00074 moles, 1 eq) in DMF (25 mL), EDCI (0.157 g., 0.00082 moles, 1.1 eq), HOBt (0.126 g, 6 0.00082 moles, 1.1 eq) and DIPEA (0.48 mL, 0.0026 moles, 3.5 eq) were added at 0° C. and stirred for 15 minutes. A 0249 General procedure for Compound 1: To a solution of Solution of 1-2-(methoxyphenyl)piperazine (Compound 6. 4-bromo phenol (5.0, 0.0289 moles, 1 eq) in DMF (50 mL), 0.171 g, 0.00074 moles, 1 eq) was then added at 0°C. and then potassium carbonate (9.970 g., 0.0722 moles, 2.5 eq) was the resulting mixture was allowed to stir at room temperature added followed by the addition of ethyl iodide (4.70 ml, for overnight. After completion of the reaction, water (30 mL) 0.0578 moles, 2 eq) and stirred for overnight. The progress of was added and extracted with ethyl acetate (2x30 mL). The the reaction was monitored by TLC. After completion of combined organic layer was dried over anhydrous Na2SO starting material, the reaction mixture was quenched with and concentrated under reduced pressure. The crude product water (25 mL) and extracted with ethylacetate (2x50 mL). was dissolved in EtOAc and to this pentane was added to yield The combined organic layers were washed with brine (40 ml) compound 7 as a white solid which was filtered and dried (200 solution. Ethylacetate layer was dried over NaSO and con mg, 46.5% yield). centrated under reduced pressure. The crude product was purified by column chromatography (9:1, ethyl acetate/hex ane) to obtain compound 1 (5.0g, 86.2%). MS (201.06) 202.1 (M+1). 0250 General procedure for Compound 2: Compound 1 was taken in a two necked flask (2.00 g, 0.0099 moles, 1 eq). Chlorosulfonic acid (25 mL, 0.358 moles, 36 eq) was added slowly over a period of 10 min at -10° C. The resulting mixture was stirred at the same temperature for 10 min. After completion of the starting material, the reaction mixture was poured into ice cold water (100 mL) and extracted with ethyl acetate. The organic layer was washed with HO, dried over Br NaSO and concentrated under reduced pressure. The desired product 2 was obtained by column purification (60 0256 H NMR (500 MHz, DMSO-d) 1.30 (t,3H), 2.80 120 mesh silica gel, 5% ethyl acetate-hexane) as a Solid (3 g, 3.0 (bs, 4H), 3.30-3.60 (bm, 4H), 3.78 (s.3H), 4.20 (q, 2H), 43.3%). 6.80-7.00 (m, 4H), 7.10-7.20 (m, 3H), 7.30-7.34 (d. 2H), 0251 General procedure for Compound 3: To a solution of 7.70-7.75 (dd. 1H), 7.80 (d. 1H), 10.35 (s, 1H); MS 574.0; MS ethyl-4-aminobenzoate (300 mg, 1.81 mmole, 1 eq) in 1:1 base peak at 574.0; HPLC purity 97.80%. mixture of DCM/pyridine (5 mL/5 mL) was added a solution of 5-bromo-2-ethoxybenzene-1-sulfonyl chloride (com Synthesis of Compound 6 pound 2,654 mg, 2.17 mmole, 1.2 eq) in DCM (5 mL/5 mL) at 0°C. The reaction mixture was then allowed to stir at room temperature for overnight. After completion of the reaction, 0257 the reaction mixture was diluted with DCM and washed with water, dried over Sodium Sulphate and concentrated under Scheme 3: reduced pressure. The crude product was then washed with diethyl ether followed by n-hexane and dried to yield com MeO pound 3 as an off white solid (0.600 g, 77%). / \ BINAP, BocN NH -- Pol(OAc)2 0252 H NMR (200 MHz, DMSO-d) 1.30 (t, 3H), 1.58 ocN A. Br Cs2CO3, (t, 3H), 4.20-4.40 (m, 4H), 6.82 (d. 1H), 7.10-7.20 (m, 2H), 1,4-dioxane, 7.56-7.60 (dd. 1H), 7.90-8.00 (m, 3H). 80° C., 0253 General procedure for Compound 4: Ethyl 4-(5- overnight bromo-2-ethoxyphenylslulfonamido) benzoate (compound MeO 3, 600 mg, 0.0014 moles, 1 eq) was taken in THF HO (1:1, / \ Herether HC 30 mL/30 mL). LiOH.HO (0.293 g, 0.007 moles, 5 eq) was rt, 2h then added to the above reaction mixture and stirred at reflux for overnight. After completion of the starting material, the solvent was removed under reduced pressure to obtain the crude product. The crude product was washed with ethyl US 2010/0331307 A1 Dec. 30, 2010
0263 Compound 8 was prepared from commercially -continued available 2-Methoxy-5-chlorobenzenesulfonyl chloride as shown in Scheme 2. 0264 H NMR (500 MHz, DMSO-d) 2.8-3.0 (bm, 4H), CIHoHN N 3.40-3.78 (m, 4H), 3.80 (s.3H), 3.84 (s, 3H), 6.80-7.00 (m, 4H), 7.12 (d. 2H), 7.21 (d. 1H), 7.30 (d. 2H), 7.65 (dd. 1H), 6 7.74 (d. 1H); MS base peak at m/z,516; HPLC purity: 94.33%
0258 General procedure for Compound 5: In a two neck 5-Bromo-2-methoxy-N-(4-(4-(2-methoxyphenyl) round bottom flask, tert-butylpiperazine-1-carboxylate (4.97 piperazine-1-carbonyl)phenyl)benzene-Sulfonamide g, 0.0267 moles, 1 eq), 2-bromo anisole (5.0 g, 0.0267 moles, (9) 1 eq) and CSCO (21.7 g., 0.0668 moles, 2.5 eq) were charged in degassed 1,4-dioxane (100 mL) under N2 atmo 0265 sphere. BINAP (1.49 g, 0.00240 moles, 0.09 eq) and Pd (OAc). (0.96 g., 0.00042 moles, 0.016 eq) were then added to the reaction mixture under N atmosphere and stirred at 80° 9 C. for overnight. The progress of the reaction was monitored by TLC. After completion of the starting material, the excess / No O. O O of solvent was distilled off under reduced pressure and the M/ residue was diluted with water and extracted with ethyl acetate. The organic layer was separated, dried over NaSO N C-N N and concentrated under reduced pressure. The crude product '-O--O-)H I was purified by column chromatography (silica gel 60-120, 5-6%, ethyl acetate/hexane) to yield the desired product 5 as viscous oil (2.8 g., 36%). Br (0259 'H NMR (500 MHz, CDC1): 142 (s, 9H), 3.0 (m, 4H), 3.60 (m, 4H), 3.84 (s.3H), 6.80-7.00 (m, 4H); MS 293.1 0266 The corresponding sulfonyl chloride was prepared (M+1 peak). from 4-bromophenol. O-Methylation of 4-bromophenol fol 0260 General procedure for Compound 6: In a two neck lowed by chlorosulfonic acid reaction gave 2-methoxy-5- RB flask, tert-butyl-4-(2-methoxyphenyl)piperazine-1-car bromobenzenesulfonyl chloride which was utilized to pro boxylate (compound 5, 0.600 g, 0.00205 moles, 1 eq) was duce compound 9 as provided in Scheme 2. treated with ether-HCl (10 mL). The resulting mixture was 0267 H NMR (500 MHz, DMSO-d) 2.90-3.00 (bm, stirred for overnight. After completion of the starting material 4H), 3.40-3.78 (m, 4H), 3.80 (s.3H), 3.84 (s.3H), 6.80-7.00 as indicated by TLC, ether was removed under reduced pres (m, 4H), 7.10-7.18 (m,3H), 7.30 (d. 2H), 7.70 (dd. 1H), 7.74 sure and a solid material was obtained. The solid material was (d. 1H); MS base peak at 562.0; HPLC purity: 94.36% washed with ethyl acetate and dried to obtain the amine compound 6 as a white solid (0.425 g, 90.08%). N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) 0261 The following analogs were prepared utilizing the phenyl)naphthalene-2-sulfonamide (10) above procedure with various sulfonyl chlorides in place of compound 2. 0268 5-Chloro-2-methoxy-N-(4-(4-(2-methoxyphenyl) piperazine-1-carbonyl)phenyl)benzene-Sulfonamide 10 (8) / 0262 O O O
8 No / V / 0269 Commercially available naphthalene-2-sulfonyl chloride was utilized in place of compound 2 used to provide N C-N N H I 10. S-()--O 0270 "H NMR (500 MHz, DMSO-d) 2.80-3.00 (bm, 4H), 3.40-3.78 (m, 4H), 3.80 (s, 3H), 6.80-7.00 (m, 4H), C 7.10-7.30 (m, 4H), 7.60-7.80 (m, 3H), 8.00-8.20 (m, 3H), 8.50 (s, 1H), 10.7 (s, 1H); MS base peak at 504.2: HPLC purity: 93.65% (HPLC) US 2010/0331307 A1 Dec. 30, 2010 20
5-Chloro-2-ethoxy-N-(4-(4-(2-methoxyphenyl)pip 0278 Compound 13 was prepared following Scheme 2 erazine-1-carbonyl)phenyl)benzene-Sulfonamide using commercially available naphthalene-1-sulfonyl chlo (11) ride. 0271 0279 HNMR (500 MHz, DMSO-d) 2.90-3.00 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80 (s.3H), 6.84-6.98 (m, 4H), 7.10 (d. 11 2H), 7.24 (d. 2H), 7.62-7.78 (m, 3H), 8.08 (d. 1H), 8.23 (d. 1H), 8.28 (d. 1H), 8.72 (d. 1H), 10.98 (s, 1H); MS base peak O 1no O. O. at 502.1; HPLC purity 96.59%. MA - N C-N N 2,6-Difluoro-N-(4-(4-(2-methoxyphenyl)piperazine -( ) -O 1-carbonyl)phenyl)benzene-sulfonamide (14)
C 0280
0272. The corresponding sulfonyl chloride was prepared from 4-chlorophenol. O-Ethylation of 4-chlorophenol fol lowed by a chlorosulfonic acid reaction under the appropriate conditions provided 2-ethoxy-5-chlorobenzenesulfonyl 14 chloride which was utilized to prepare compound 11 as shown in Scheme 2. 0273 H NMR (500 MHz, DMSO-d) 1.30 (t,3H), 2.80 / 3.0 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80 (s.3H), 4.20 (q, 2H), 6.80-7.00 (m, 4H), 7.16 (d. 2H), 7.20 (d. 1H), 7.38 (d. 2H), 7.60 (d. 1H), 7.80 (s, 1H), 10.20 (s, 1H); MS base peak at '-O--O-R)H l 530.1; HPLC purity 97.48% N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) phenyl)benzene-sulfonamide (12) 0281 Compound 14 was prepared following Scheme 2 0274 using commercially available 2,6-difluorobenzenesulfonyl chloride. 12 (0282 'HNMR (500 MHz, DMSO-d)2.90-3.00 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80 (s.3H), 6.84-7.00 (m, 4H), 7.20 (d. ? 2H), 7.30 (t, 2H), 7.38 (d. 2H), 7.68-7.74 (m. 1H), 11.2 (s, 1H); MS base peak at 488.1; HPLC purity 97.16%. p-O--O-R) N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) ( ). A| \ / phenyl)cquinoline-8-sulfonamide (15) (0283 0275 Compound 12 was prepared following Scheme 2 using benzenesulfonyl chloride. 0276 H NMR (500 MHz, DMSO-d)2.90-3.00 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80 (s.3H), 6.84-6.98 (m, 4H), 7.15 (d. 2H), 7.30 (d. 2H), 7.56-7.64 (m, 3H), 7.80 (d. 2H), 10.6 (s, 15 1H); MS base peak at 452.6; HPLC purity 96.90%. / N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) O. O O phenyl)naphthalene-1-sulfonamide (13) r VM (0277 N C-N N '-O--O-R)H I 13 / 0284 Compound 15 was prepared following Scheme 2 O. O O using commercially available quinoline-8-sulfonyl chloride. VA 0285 H NMR (500 MHz, DMSO-d) 2.90-3.00 (bs, 4H), N C-N N 3.40-3.78 (bm, 4H), 3.80 (s.3H), 6.82 (d. 2H), 6.90-7.00 (m, Orik'-O--O-R) 2H), 7.15-7.20 (2 doublets, 4H), 7.70-7.78 (m, 2H), 8.24 (d. 1H), 8.40 (d. 1H), 8.50 (d. 1H), 9.15 (bs, 1H), 10.42 (s, 1H): MS base peak at 503.2; HPLC purity 97.11%. US 2010/0331307 A1 Dec. 30, 2010
N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) 0293 Compound 19 was prepared from commercially phenyl)benzodthiazole-5-sulfonamide (17) available 2,3-dihydrobenzodioxo-6-sulfonyl chloride follow 0286 ing the protocol provided in Scheme 2. 0294 H NMR (500 MHz, DMSO-d) 2.80-3.00 (m, 4H), 3.42-3.78 (bm, 4H), 3.80 (s.3H), 4.25 (m, 4H), 6.86-6.88 (m, 17 2H), 6.92-6.98 (m, 2H), 7.00 (d. 1H), 7.15 (d. 2H), 7.24 (s, 1H), 7.26-7.30 (dd. 1H), 7.34 (d. 2H), 10.5 (s, 1H); MS base peak at 510.3: HPLC purity 97.02%. 5-Chloro-2-methoxy-N-(4-(4-(2-methoxyphenyl)-1, 4-diazepane-1-carbonyl)phenyl)benzene-Sulfona mide (19a) 0287 Compound 17 was prepared from commercially available benzthiazole-6-sulfonyl chloride following the 0295) Scheme 2 protocol. 0288 H NMR (500 MHz, DMSO-d)2.90-3.00 (bs, 4H), 19a 3.40-3.78 (bm, 4H), 3.80 (s.3H), 6.82-7.00 (m, 4H), 7.20 (d. 2H), 7.38 (d. 2H), 7.90 (d. 1H),8.22(d. 1H),8.78 (s, 1H),9.60 No O O H3CO (s, 1H), 10.70 (s, 1H); MS base peak at 509. 1; HPLC purity MA 97.29% N C-N N N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) '-O-O-R)H I N / phenyl)-3,5-dimethylbenzene-sulfonamide (18) 0289 C
18 0296 Compound 19a was prepared according to Scheme 2. N-boc-homopiperazine was utilized in place of N-Boc piperazine to prepare the N-2-methoxyphenyl-homopipera Zine intermediate through a Buchwald reaction as provided in Scheme 3. 0297 H NMR (500 MHz, DMSO-d) 1.70 (s, 1H), 1.90 (s, 1H), 3.10-3.40 (m, 9H), 3.60-3.80 (m, 2H), 3.82 (s.3H), 6.70-6.82 (m, 4H), 6.96-7.30 (m, 5H), 7.66 (t, 1H), 7.74 (s, 1H), 10.40 (d. 1H); MS base peak at 530.1; HPLC purity 95.89%. 0290 Compound 18 was prepared from commercially available 3,5-dimethylbenzenesulfonyl chloride following the protocol provided in Scheme 2. N-(4-(4-(2-methoxyphenyl)-1,4-diazepane-1-carbo 0291 'H NMR (500 MHz, DMSO-d) 2.35 (s, 6H), 2.80 nyl)phenyl)cquinoline-8-sulfonamide (19b) 2.90 (m, 4H), 3.42-3.78 (bm, 4H), 3.80 (s.3H), 6.88 (bs, 2H), 6.92-7.00 (m, 2H), 7.15 (d. 2H), 7.26 (s, 1H), 7.33 (d. 2H), 0298 7.42 (s. 2H), 10.5 (s, 1H); MS base peak at 480.3: HPLC purity 98.56%. 19b N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) phenyl)2,3-dihydrobenzob 14-dioxine-6-sulfona mide (19) / 0292 N (r- OCH 19 j\,O / / O \, O O V/PY M. V. N C-N N 0299 H NMR (500 MHz, DMSO-d) 1.70 (s, 1H), 1.90 (s, 1H), 3.10-3.40 (m, 8H), 3.58-3.80 (m, 3H), 6.58 (d. 1H), Cri-)--CO 6.70–7.20 (m, 7H), 7.80 (m, 2H), 8.30 (t, 1H), 8.40 (d. 1H), 8.56 (t, 1H), 9.18 (s, 1H), 10.40 (d. 1H); MS base peak at 517.2: HPLC purity 97.60%. US 2010/0331307 A1 Dec. 30, 2010 22
N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) phenyl)-2-methylbenzodthiazole-4-sulfonamide -continued COOEt (35) OMe 0300 O2 S n N H LiOH 35 THF-HO (9:1) N H3CO C )- R / 2O N C-N N COOH / M | OMe HN N O O \ / S n N (23) H H EDCL, HOBt 0301 2-methylbenzothiazole-4-sulfonyl chloride was DIPEA, DMF, prepared according to U.S. Pat. No. 4,643,759. Compound 35 12 h, rt was prepared following the general procedure described in C Scheme 2. 21 0302) H NMR (500 MHz, DMSO-d) 2.80 (s.3H), 3.00 \ (bs, 4H), 3.40-3.78 (m, 4H), 3.80 (s.3H), 6.90 (s. 2H), 6.90 7.0 (m, 2H), 7.18 (d. 2H), 7.30 (d. 2H), 7.82 (d. 1H), 8.04 (d. 1H), 8.60 (s, 1H), 10.6 (1H); MS base peak at 523.4: LCMS - ) i-O-( ) purity 97.38% | N-(4-(4-(2-methoxyphenyl)piperazine-1-carbonyl) (S - phenyl)thiophene-2-sulfonamide (36) compound 24 Compound 22: 0303 Br
36 BINAP, Pd(OAc), BocN NH + He O. O HCO Cs2CO3, 1,4-dioxane, V/ 80° C., 12h N C-N N A V ether? HC y BocN N -e- Y-5-)--O V / rt, 2h 22 0304 Compound 36 was prepared from commercially available thiophene-2-sulfonyl chloride according to the gen CIHoHN N eral procedure described in Scheme 2. 0305 H NMR (500 MHz, DMSO-d)2.90-3.00 (bs, 4H), 23 3.30-3.78 (bm, 4H), 3.80 (s.3H), 6.80-6.90 (m, 2H), 6.90-7.0 (m. 2H), 7.18 (d. 1H), 7.20 (d. 2H), 7.40 (d. 2H), 7.60 (s, 1H), 7.94 (d. 1H), 10.70 (s, 1H); MS base peak at 458.2: HPLC 0307 Procedure for the synthesis of compound 20: To a purity 95.02%. solution of 2-methoxy-5-chlorobenzenesulfonyl chloride (87.8 mg 0.00362 moles, 1.5 eq) in dichloromethane was Synthesis of Phenyl Analogues added a solution of ethyl 4-aminobenzoate (400 mg, 0.00242 moles, 1 eq) in 1:1 ratio of pyridine and DCM (5 mL/5 mL) under nitrogen atmosphere at 0°C. The reaction mixture was 0306 stirred at room temperature overnight. The progress of the reaction was monitored by TLC. Upon completion, the reac tion mixture was diluted with DCM, washed twice with water, Scheme 4 and dried with anhydrous Sodium Sulphate. The organic layer OMe was concentrated, dried, washed with ether followed by n-hexane and dried to provide 20 as an off-white solid (0.8 g. SOCI is-( )-cool 89% yield). -e- (0308 H NMR (500 MHz, CDC1,) 1.34 (t, 3H), 4.0 (s, Pyridine, DCM, 12 h. 3H), 4.22-4.32 (q, 2H), 6.90 (d. 1H), 7.16 (d. 2H), 7.20 (s, rt 1H), 7.84 (s, 1H), 7.92 (d. 2H). C (0309 Procedure for the synthesis of compound 21: LiOH (226 mg, 0.0049 moles, 4 eq) was added to a stirred solution US 2010/0331307 A1 Dec. 30, 2010 of compound 20 (500 mg, 0.0013 moles, 1 eq) in THF HO N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)benze mixture (1:1 ration, 30 ml/30 ml) and heated at reflux over nesulfonamide (25) night. The progress of the reaction was monitored by TLC. Upon completion, the reaction mixture was acidified with 0317 citric acid to pH 4 and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sul 25 fate and distilled. The resulting solid 21 was dried and used without purification in the following step (400 mg, 87% O yield). W / \ 0310 "H NMR (500 MHz, DMSO-d)3.82 (s.3H), 7.10 N C-N N 7.22 (m, 3H), 7.62 (d. 1H), 7.88-7.92 (m, 3H), 10.64 (s, 1H), C*-O-O-O 12.70 (s, 1H). 0311 Procedure for the synthesis of compound 22: The 0318 Compound 25 was prepared using benzenesulfonyl synthesis of compound 22 was carried out following a proce chloride following a protocol similar to that shown in Scheme dure similar to compound 5 utilizing bromobenzene in place 4. of 2-bromoanisole. MS 263 (M+1 peak). 0319 HNMR (500 MHz, DMSO-d)3.10-3.20 (bs, 4H), 0312 Procedure for the synthesis of compound 23: Com 3.40-3.78 (bm, 4H), 6.80 (t, 1H), 6.92 (d. 2H), 7.10-7.35 (m, pound 22 (500mg) was dissolved in 30 ml of ether/HCl and 6H), 7.50-7.70 (m,3H), 7.80 (d. 2H), 10.60 (s, 1H); MS base stirred for 2 hrs at room temperature under a nitrogen atmo peak at 422.0; HPLC purity 97.92%. sphere. The reaction mixture was distilled under reduced pressure to remove ether, washed with pentane and dried over 4-Fluoro-N-(4-(4-phenylpiperazine-1-carbonyl)phe sodium sulfate to obtain compound 23 (300 mg, 97% yield). nyl)benzenesulfonamide (26) 0313 "H NMR (500 MHz, DMSO-d)3.10-3.20 (m, 4H), 3.40-3.42 (m, 4H), 6.80 (t, 1H), 7.00 (d. 2H), 7.22 (t, 2H), 9.0 0320 (bs, 1H), 9.40 (bs, 2H). 0314 Procedure for the synthesis of compound 24: To a 26 stirred solution of compound 21 (100 mg, 0.00029 moles, 1 O O eq) in DMF (10 mL) was added EDCI (62 mg, 0.00032 moles, V/ 1.1 eq), HOBt (50 mg, 0.00032 moles, 1.1 eq) and DIPEA Sn (0.16 ml, 0.00088 moles, 3 eq) at 0° C. under a nitrogen N C-N N atmosphere. The reaction mixture was stirred for 5 minutes at 0° C. and then at room temperature for 30 minutes. A solution F Ori ( ) - ) of compound 23 (59 mg 0.00029 moles, 1 eq) dissolved in DMF and half equivalent of DIPEA was added slowly to the 0321 Compound 26 was made using 4-fluorobenzene above reaction mixture at 0° C. and allowed to stir at room sulfonyl chloride following a similar procedure as provided in temperature overnight. The reaction was monitored by TLC. Scheme 4. Upon completion, the reaction mixture was washed with 0322 'HNMR (500 MHz, DMSO-d)3.10-3.20 (bs, 4H), water and extracted with ethyl acetate. The organic layer was 3.40-3.80 (bm, 4H), 6.80 (t, 1H), 6.94 (d. 2H), 7.14 (d. 2H), dried over Sodium Sulfate and concentrated under vacuum. 7.20 (t, 2H), 7.32 (d. 2H), 7.35 (t, 2H), 7.80-7.90 (m, 2H), The crude product was purified by crystallization with an 10.6 (s, 1H); MS base peak at 440.1; HPLC purity 96.72%. ethyl acetate/hexane solvent mixture to obtain compound 24 in 24.6% yield (35 mg). 3-Chloro-N-(4-(4-phenylpiperazine-1-carbonyl)phe nyl)benzenesulfonamide (27) 24 0323 N O V/ 27 N C-N N S-()--O-(H I ) V/ "nn-K)--O-K)N C-N N C
0315 H NMR (500 MHz, DMSO-d)3.10-3.20 (bs, 4H), 0324 Compound 27 was prepared using ommercial 3.40-3.78 (bm, 4H), 3.82 (s, 3H), 6.80 (t, 1H), 6.90 (d. 2H), 3-chlorobenzenesulfonyl chloride following a similar proce 7.14 (d. 2H), 7.20 (t, 3H), 7.30 (d. 2H), 7.62-7.66 (dd. 1H), dure as provided in Scheme 4. 7.74 (d. 1H), 10.40 (s, 1H); MS base peak at 486.0; HPLC 0325 H NMR (500 MHz, DMSO-d)3.10-3.20 (bs, 4H), purity 97.34%. 3.40-3.80 (bm, 4H), 6.80 (t, 1H), 7.00 (d. 2H), 7.18-7.22 (m, 0316 **Compounds 25 to 30 were prepared following a 4H), 7.38 (d. 2H), 7.60 (t, 1H), 7.70-7.80 (m, 3H), 10.6 (s, protocol similar to that described in Scheme 4. 1H); MS base peak at 456.2: HPLC purity 97.25%. US 2010/0331307 A1 Dec. 30, 2010 24
3-Methoxy-N-(4-(4-phenylpiperazine-1-carbonyl) 7.10-7.30 (m, 4H), 7.70-7.80 (m,3H), 8.10 (d. 1H), 8.20-8.30 phenyl)benzenesulfonamide (28) (m. 2H), 8.76 (d. 1H), 11.0 (s, 1H); MS base peak at 472.3: HPLC purity 99.14%. 0326 N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)cquino line-8-sulfonamide (30a) 28 0335) O O V/ N C-N N 30a o'-O--C NN V/ SN W 0327 Compound 28 was prepared using 3-methoxyben N C-N N Zenesulfonyl chloride according to the general procedure pro H \ / vided in Scheme 4. 0328 H NMR (500 MHz, DMSO-d)3.10-3.20 (bs, 4H), 3.40-3.78 (bm, 4H), 3.80 (s, 3H), 6.80 (t, 1H), 6.95 (d. 2H), 0336 H NMR (500 MHz, DMSO-d) 3.00-3.20 (bm, 7.14-7.24 (m, 5H), 7.28 (bs, 1H), 7.32-7.40 (m, 3H), 7.50 (t, 4H), 3.30-3.70 (bs, 4H), 6.80 (t, 1H), 6.90 (d. 2H), 7.10-7.22 1H), 10.6 (s, 1H); MS base peak at 452.2: HPLC purity (m, 6H), 7.70-7.80 (m, 2H), 8.30 (d. 1H), 8.44 (d. 1H), 8.56 93.60%. (d. 1H), 9.18 (d. 1H), 10.42 (s, 1H); MS base peak at 473.2: HPLC purity 98.50%. 2-Chloro-N-(4-(4-phenylpiperazine-1-carbonyl)phe nyl)benzenesulfonamide (29) Synthesis of 4-Methoxy Phenyl Analogues 0337 0329
Scheme 5: 29 COOH M. v. C O O OMe O HN \ / N-(y-o. N C-N N SNNH (32)32 H EDCL, HOBt C*-O- O O-() DIPEA, DMF, C 12 h, rt 0330 Compound 29 was prepared using commercially 21 available 2-chlorobenzenesulfonyl chloride according to the general procedure provided in Scheme 4. Y, 0331 'H NMR (500 MHz, DMSO-d)3.10-3.20 (bs, 4H), y-K)--O-()-ol 3.40-3.78 (bm, 4H), 6.80 (t, 1H), 6.95 (d. 2H), 7.16-7.38 (m, so \ / 6H), 7.58 (t, 1H), 7.64 (d. 2H), 8.10 (d. 1H), 10.90 (s, 1H); MS O base peak at 456.2: HPLC purity 99.21%. C compound 33 N-(4-(4-phenylpiperazine-1-carbonyl)phenyl)naph Compound 31: thalene-1-sulfonamide (30) Br 0332 M V BINAP, Pd(OAc), BocN NH + Her V ? Cs2CO3 30 1,4-dioxane, 80°C. 12h OCH 'V' A V ether HC N C-N N BocN N OCH - -> SS-K)--O-( ) V v rt, 2h Orik 31
0333 Compound 30 was prepared using commercially CHOHN N OCH available naphthalene-1-sulfonyl chloride according to the general procedure provided in Scheme 4. 32 0334 H NMR (500 MHz, DMSO-d)3.10-3.20 (bs, 4H), 3.40-3.78 (bm, 4H), 6.80 (t, 1H), 6.95 (d. 2H), 7.08 (d. 2H), US 2010/0331307 A1 Dec. 30, 2010
Synthesis of Compound 31 0344 Compound 34 was prepared following the general protocol provided in Scheme 4 starting from 2-methoxy-4- 0338 To a solution of 4-bromoanisole (2.0 g, 0.0106 fluorobenzenesulfonyl chloride. moles, 1 eq) in 1,4-dioxane (30 mL), Nagas was purged for 30 minutes at room temperature followed by the addition of (0345 H NMR (500MHz, DMSO-d)3.00 (bs, 4H), 3.40 CsCO (7.64 g., 0.023 moles, 2.2 eq), BINAP (598 mg, 3.70 (m, 7H), 3.82 (s.3H), 6.80-6.90 (dd, 4H), 7.14 (d. 2H), 0.00096 moles, 0.09 eq), Pd(OAc) (38 mg, 0.00017 moles, 7.20 (dd. 1H), 7.30 (d. 2H), 7.46-7.49 (m. 1H), 7.60 (dd. 1H), 0.016 eq) and tetrabutylammonium iodide (15 mg). The reac 10.4 (s, 1H); MS base peak at 500.2: HPLC purity 95.48%. tion mixture was purged with nitrogen again for another 15 minutes followed by addition of N-Boc-piperazine (2.38 g. Synthesis of 4-Chloro Pyrimidine Analogues 0.0128 moles, 1.2 eq). The reaction mixture was heated at 80° C. overnight and monitored by TLC. The excess solvent was 0346) distilled off under reduced pressure and the residue was diluted with water and extracted with ethyl acetate. The organic layer was separated, washed once again with water, Scheme 6: dried over sodium sulfate and concentrated. The crude mate OMe rial was purified by column chromatography using 60-120 mesh silica gel (15% Ethyl acetate/hexane) to afford 1.5 g. SOCI is-( )- COOEt (48.3% yield) of compound 31. H 0339 Synthesis of compound 32: Compound 31 was Pyridine, DCM, 12 h. stirred at room temperature for 2 hrs in 60 ml of ether/HC1. rt The excess of solvent was removed under reduced pressure C and the resultant solid was washed with n-hexane and dried to COOEt obtain 780 mg (99.7% yield) of compound 32. OMe O 5-Chloro-2-methoxy-N-(4-(4-(4-methoxyphenyl) S n N piperazine-1-carbonyl)phenyl)benzene-Sulfonamide H LiOH (33) THF-HO 0340 (9:1) C 2O 33 N HN N W \ No O O COOH w OMe NF \% / V O2 NN C-N N OMe S n N C H \ / J \ / H (38) EDCL, HOBt DIPEA, DMF, C 12 h, rt C 0341 Compound 33 was prepared following the protocol 21 described for compound 24 in Scheme 4. 0342 'HNMR (500MHz, DMSO-d)3.00 (bs, 4H), 3.40 3.70 (m, 7H), 3.80 (s.3H), 6.80-6.90 (dd, 4H), 7.14 (d. 2H), 7.22 (d. 1H), 7.30 (d. 2H), 7.62-7.66 (dd. 1H), 7.74 (d. 1H), p.AEO () i-y V / N-(N / 10.4 (s, 1H); MS base peak at 557.1; HPLC purity 94.14%. y C 5-Fluoro-2-methoxy-N-(4-(4-(4-methoxyphenyl) C piperazine-1-carbonyl)phenyl)benzene-Sulfonamide compound 39 (34) Compound 38: 0343
M N N211. NN NaHCO3, EtOH 34 BocN NH + - - v M reIllux, S C No V N Sn E v B N Y ether? HC N C-N N OMe OC He H | V / V W M / rt, 2h O N C F 37 US 2010/0331307 A1 Dec. 30, 2010 26
7.22 (d. 1H), 7.36 (d. 2H), 7.66 (d. 1H), 7.80 (s, 1H), 8.18 (s, -continued 1H), 10.50 (s, 1H); MS base peak at 522.1; HPLC purity 96.50%. CIHoHN -K / N-(4-(4-(4-Chloropyrimidin-2-yl)piperazine-1-car C bonyl)phenyl)-4-fluorobenzenesulfonamide (40) 38 0353 0347 Preparation of compound 37: 2,4-dichloropyrimi dine (801 mg 0.0053 mole, 1 eq), N-Boc-piperazine (1.0gm. 40 0.0053 mole, 1 eq) and sodium bicarbonate (903 mg 0.0107 O. O mole, 2 eq) were dissolved in ethanol (50 ml) and stirred at MA o reflux for 1 h. Progress of the reaction was monitored by TLC. Y / V N The excess solvent was removed, dissolved in water and N C-N N-K / extracted with DCM. The organic layer was washed with \ / Y. water, dried with sodium sulfate and concentrated under F C reduced pressure. The crude product was purified on silica gel (60-120 mesh) using 15% ethyl acetate-hexane to afford coupled product compound 37 (230 mg). 0354 Compound 40 was prepared in-part by following the (0348 H NMR (500 MHz, CDC1,) 1.5 (s, 9H), 3.5 (m, protocols established for the compound 38 coupling of pyri 4H), 3.80 (m, 4H), 6.80 (d. 1H), 8.20 (d. 1H). midine as provided in Scheme 6 and subsequently by follow 0349 Preparation of compound 38: A solution of com ing general procedures as described in Scheme 4 starting pound 37 in 20 ml of ether/HCl was allowed to stir at room from 4-fluorobenzenesulfonyl chloride. temperature under nitrogen atmosphere for 1 h. The excess 0355 H NMR (500 MHz, DMSO-d)3.35-3.60(bs, 4H), solvent was distilled off under reduced pressure and the crude 3.70-3.78 (bm, 4H), 6.78 (d. 1H), 7.18 (d. 2H), 7.38 (d. 2H), material was washed with n-pentane and dried to yield 180 7.42 (d. 2H), 7.82 (d. 2H), 8.38 (d. 1H), 10.60 (s, 1H); MS mg of compound 38 in quantitative yield. base peak at 476.2: HPLC purity 97.89%. 0350 Preparation of compound 39: To a stirred solution of compound 21 (109 mg, 0.31 mmole, 1.0 eq) in DMF (15 mL), was added EDCI (67 mg, 0.35 mmoles, 1.1 eq), HOBt (53.7 Synthesis of 2-Pyrimidine Analogues mg, 0.35, 1.1 eq) and DIPEA (2.0 eq) at 0°C. under a nitrogen atmosphere. The reaction mixture was allowed to stir at room 0356 temperature for 30 minutes. A solution of compound 38 (75 mg, 0.319 mmoles, 1 eq) in 5 ml of DMF and 1.5eq of DIPEA was added slowly to reaction mixture at 0°C. and stirred at Scheme 7: room temperature for 12 h. The reaction was monitored by OMe TLC. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer SOCI in-()-cool was separated, dried over Sodium sulfate and concentrated Hes under reduced pressure. The crude product was purified on Pyridine, DCM, 12 h. silica gel column (60-120 mesh) using 2% MeOH-DCM to rt afford 30 mg of compound 39 in 18% yield. C COOEt 5-Chloro-N-(4-(4-(4-Chloropyrimidin-2-yl)pipera OMe Zine-1-carbonyl)phenyl)-2-methoxybenzenesulfona O mide (39) Sn N LiOH -e- 0351 H THF-HO (9:1)
39 C 2O N N O V/ NS SS A v OMe COOH HN N-( y N C-N N \ / OS O \ / N y \ / Y. NN (42) C H EDCL, HOBt DIPEA, DMF, C 12 h, rt C 0352 H NMR (500 MHz, DMSO-d)3.35-3.60(bs, 4H), 21 3.70-3.78 (bm, 4H), 3.80 (s.3H), 6.78 (d. 1H), 7.16 (d. 2H), US 2010/0331307 A1 Dec. 30, 2010 27
5-Chloro-2-methoxy-N-(4-(4-(pyrimidin-2-yl)pip -continued erazine-1-carbonyl)phenyl)benzene-Sulfonamide (43) 0360
43
No O. O C WW NS compound 43 SS-K)--O-K) Compound 42: I / Br C NaHCO3, EtOH BocN NH + N21 NN -e- reflux, 1 h 0361 H NMR (500 MHz, DMSO-d) 3.35-3.70 (bm, 4H), 3.70-3.80 (bm, 4H), 3.82 (s.3H), 6.62 (d. 1H), 7.15 (d. 2H), 7.22 (d. 1H), 7.34 (d. 2H), 7.62-7.66 (dd. 1H), 7.75 (d. 1H), 8.40 (s. 2H), 10.5 (s, 1H); MS base peak at 488.3: HPLC BocN N purity 97.47%. \ / 4-Chloro-N-(4-(4-(pyrimidin-2-yl)piperazine-1-car 41 bonyl)phenyl)benzenesulfonamide (44) civ/ \ –K)o 0362 44 42 Sa NE 0357 Preparation of compound 41: To a solution of 2-bro mopyrimidine (500 mg, 0.003144 moles, 1 eq) in ethanol (50 C Ori-O-O-() ml) was added sodium bicarbonate (528 mg, 0.0062 moles, 2 eq) followed by N-Boc-piperazine (585 mg, 0.0031 moles, 1.0 eq). The reaction mixture was allowed to stir at reflux for 0363 Compound 44 was prepared from 4-chlorobenzene sulfonyl chloride following the protocol described in Scheme 1 h and monitored by TLC. Upon completion, the excess 7 and utilizing the general procedure described in Scheme 4. solvent was removed under reduced pressure. The crude 0364 H NMR (500 MHz, DMSO-d) 3.35-3.70 (bm, material was diluted with water and extracted with ethyl 4H), 3.70-3.80 (bm, 4H), 6.62 (t, 1H), 7.18 (d. 2H), 7.38 (d. acetate. The organic layer was dried over Sodium Sulphate and 2H), 7.62 (d. 2H), 7.80 (d. 2H), 8.40 (d. 2H), 10.62 (s, 1H): concentrated. The crude material was washed with hexane MS base peak at 458.2: HPLC purity 98.41%. and dried to obtain 400 mg of compound 41 (48% yield). N-(4-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)phe 0358 Preparation of compound 42: A solution of com nyl)cquinoline-8-sulfonamide (45) pound 41 (400 mg) in ether/HCl (30 ml) was stirred at room temperature for 2 hrs and monitored by TLC. After 2 hrs, the 0365 reaction mixture was concentrated under reduced pressure to yield compound 42 (300 mg, 98% yield) which was subse 45 quently washed with hexane and used without purification. 0359 Preparation of compound 43: To a solution of com NN O O pound 21 (100 mg 0.00029 moles, 1 eq) in DMF (15 mL) was YMA / \ N o added EDCI (61.5 mg, 0.00032 moles, 1.1), HOBt (49.28 mg, N C-N N-( / 0.00032 moles, 1.1 eq) and 1.5 equivalents of DIPEA at 0°C. | \ / Y. and stirred at room temperature for 30 minutes. To this, a solution of compound 42 in DMF (5 ml) and 2 eq of DIPEA 0366 Compound 45 was prepared from 4-chlorobenzene was added at 0°C. and stirred at room temperature overnight. sulfonyl chloride following the protocol described in Scheme The reaction mixture was quenched with water and extracted 7 using the general procedure provided in Scheme 4. with ethyl acetate. The organic layer was washed with water, 0367 "H NMR (500 MHz, DMSO-d) 3.30-3.80 (bm, dried over sodium sulfate and concentrated under reduced 8H), 6.62 (t, 1H), 7.18 (d. 2H), 7.22 (d. 2H), 7.64-7.80 (m, pressure to provide the crude product. The crude material was 2H), 8.30 (d. 1H), 8.38 (d. 2H), 8.42 (d. 1H), 8.58 (d. 1H), purified on a silica gel (230-400 mesh) column with 3% 9.18 (d. 1H), 10.42 (s, 1H); MS base peak at 475.2: HPLC MeOH/DCM to yield compound 43 in 31.6% yield (45 mg). purity 99.52%. US 2010/0331307 A1 Dec. 30, 2010 28
Synthesis of Pyrazine Analogues removed under reduced pressure and the crude material was diluted with water and extracted with ethyl acetate. The 0368 organic layer was dried over Sodium sulfate and concentrated. The crude material was washed, purified on silica gel (60-120 mesh) using 30% ethylacetate-hexane to provide 400 mg of Scheme 8: compound 46 (44.1% yield). OMe 0370 Preparation of compound 47: A solution of com pound 46 (250mg) in ether/HCl (30 ml) was stirred at room SOCI in-()-cool temperature for 1 h and monitored by TLC. After 1 h, the -e- reaction mixture was concentrated under reduced pressure to Pyridine, DCM, 12 h. yield compound 47 (200 mg., 98% yield) which was washed rt with hexane and used without further purification. C 0371 Preparation of compound 48: To a solution of com COOEt pound 21 (100 mg 0.00029 moles, 1 eq) in DMF (15 mL) was added EDCI (61.5 mg 0.00032 moles, 1.1), HOBt (49.28 mg, OMe O2 O 0.00032 moles, 1.1 eq) and 1.5 equivalents of DIPEA at 0°C. n and stirred at room temperature for 30 minutes. To this, a H LiOH solution of compound 47 (58.7 mg, 0.00029 moles, 1 eq) in THF-HO DMF (5 ml) and 3 eq. of DIPEA was added at 0°C. and stirred (9:1) at room temperature for 12 h. The reaction mixture was C quenched with water and extracted with ethyl acetate. The organic layer was washed with water, dried over Sodium 2O Sulfate and concentrated under reduced pressure to provide COOH / \ / v the crude product. The crude material was Subsequently puri OMe HN N O fied on silica gel (60-120 mesh) with ethyl acetate to yield S n compound 48 in 31.6% yield (45 mg). NH (47)47 EDCL, HOBt 5-Chloro-2-methoxy-N-(4-(4-(pyrazin-2-yl)pipera DIPEA, DMF, Zine-1-carbonyl)phenyl)benzene-sulfonamide (48) 12 h, rt C 0372 21
48 No V/ Y / \ EN N C-N N \ / C - ) ( ) compound 48 Compound 47: C C
/ \ N21 Cs2CO3, DMF 0373 H NMR (500 MHz, DMSO-d) 3.35-3.70 (bm, BocN NH + | - 8H), 3.82 (s, 3H), 7.14 (d. 2H), 7.22 (d. 1H), 7.33 (d. 2H), N N 100° C., 12h 7.62-7.68 (dd. 1H), 7.74 (d. 1H), 7.86 (d. 1H), 8.10 (bs, 1H), 8.30 (s, 1H), 10.56 (s, 1H); MS base peak at 488.2: HPLC N purity 92.55%. B OC N Y. --ether? HC V / \ / rt, 2h N N-(4-(4-(pyrazin-2-yl)piperazine-1-carbonyl)phenyl) 46 quinoline-8-sulfonamide (49) / \ EN 0374 CHOHN\ / -(N / 47 49 NN 0369 Preparation of compound 46: To a solution of W V =N 2-chloropyrazine (500 mg, 0.0027 moles, 1 eq) in DMF (20 Ya ml) was added cesium carbonate (1.7g, 0.0052 moles, 2 eq) N N N -() followed by N-Boc-piperazine (506.8 mg, 0.0027 moles, 1.0 eq). The reaction mixture was heated at 100° C. for 12hrs and monitored by TLC. Upon completion, the excess solvent was US 2010/0331307 A1 Dec. 30, 2010 29
0375 Compound 49 was prepared from quinoline-8-sul material remaining and continuation of the reaction failed to fonyl chloride as described in Scheme 8 using the general show improvement. The reaction mixture was quenched with procedure provided in Scheme 4. water and extracted with ethyl acetate. The organic layer was separated, dried over Sodium sulfate and concentrated under 0376) "H NMR (500 MHz, DMSO-d) 3.35-3.70 (bm, reduced pressure. The crude product 50 containing 50% of 8H), 7.12 (d. 2H), 7.22 (d. 2H), 7.68-7.78 (m, 2H), 7.84 (s, the startingester was used without further purifications for the 1H),8.08 (s, 1H), 8.24 (d. 2H), 8.42 (d. 1H),8.52 (d. 1H),9.19 next step. (s, 1H), 10.50 (s, 1H); MS base peak at 475.2: HPLC purity 0379 Preparation of compound 51: To a solution of com 98.10%. pound 50 (270mg) in THF/HO was added lithium hydroxide (0.160 g, 5 eq, 3.786 mmole). The resulting reaction mixture Synthesis of Pyridine Analogues was heated to reflux and stirred for 4 hrs. Upon completion, the reaction mixture was diluted with water and extracted 0377 with ethyl. The aqueous layer was acidified with citric acid and extracted with ethyl acetate. The organic layer was sepa rated and dried over Sodium Sulfate and concentrated under Scheme 9: reduced pressure. The crude acid 51 (90 mg, 36% yield) used without further purification. OMe 0380 Preparation of compound 52: To a solution of com pound 51 (90 mg, 0.263 mmole, 1 eq) in DMF (15 mL) was added PyBOP (205 mg, 0.395 mmole, 1.5 eq) at 0° C. and SOCI in-()-co.NR stirred for 5 minutes. To this, a solution of compound 6 (60.2 NaH, DMF, rt mg, 0.2635 mmole, 1 eq) in 5 ml of DMF and 3 eq of DIPEA 2.5 hrs was added at 0°C. and stirred at room temperature overnight. Upon completion, the excess solvent was removed in vacuo C and the residue was diluted with water and extracted with COOEt OMe 21 ethyl acetate. The organic layer was separated, washed with water and dried over Sodium Sulfate and concentrated under S N reduced pressure. The crude product was purified by silica gel NNH N LiOH column chromatography (60-120 mesh) using 1-2% MeOH/ THF-HO DCM to yield compound 52 in 33% yield (45 mg). 5-Chloro-2-methoxy-N-(5-(4-(2-methoxyphenyl) (9:1) piperazine-1-carbonyl)pyridin-2-yl)benzenesulfona C mide (52) 50 0381
HN N OMe 21 COOH \ / 52 O HCO Sa Sa 3 N N 6 No / H Her PyBOP VSN / o / V DIPEA, DMF, 12 h, rt N \ / C-N N C N / I \ / 51
C 0382 'HNMR (500MHz, DMSO-d)3.00 (bs, 4H), 3.40 OMe 3.78 (bm, 4H), 3.9 (s, 6H), 6.90 (s. 2H), 6.92-7.00 (m, 2H), 7.20 (d. 1H), 7.60-7.62 (m. 1H), 7.80-7.82 (m, 2H), 8.18 (s, 1H), 11.4 (bs, 1H); MS base peak at 517.2: HPLC purity OMe N 97.65%. HN N-(5-(4-(2-methoxyphenyl)piperazine-1-carbonyl) y \ / pyridin-2-yl)guinoline-8-sulfonamide (53) C 7\ N O 0383 O O 52 53 0378 Preparation of compound 50: To a suspension of NaH (94 mg. 3.94 mmole, 2 eq) in DMF (20 mL) was added NN / methyl-2-amino-pyridine-5-carboxylate (300 mg, 1.97 V/ mmole, 1 eq) and stirred at room temperature for 30 minutes. A solution of 5-chloro-2-methoxybenzenesulfonyl chloride '-O--O-K)H \ A. y (570 mg, 2.36 mmole, 1.2 eq) was added slowly at room temperature and stirred for an additional 2 hrs. The reaction was monitored by TLC which showed 50% of the starting