(1))998++3.2+5+6.8(2)12-(1+2)(9)400÷125÷8(3)(-)×12(10)1×2×(11)34×(2+)(18)125×8.8(4)4.35+4.25+3.65+3.75(12)3.4×99+3.4(19)17.15-8.47-1.53(5)17-3-4(13)÷2+×(20)0.125×0.25×32(6) 题目和参考答案——精英家教网——
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（1）（8）998+1246（16）4+3.2+5+6.8（2）12-（1+2）（9）400÷125÷8（17）25×（37×8）（3）（-）×12（10）1×2×（11）34×（2+）（18）125×8.8（4）4.35+4.25+3.65+3.75（12）3.4×99+3.4（19）17.15-8.47-1.53（5）17-3-4（13）÷2+×（20）0.125×0.25×32（6）22.3-2.45-5.3-4.55（14）（++）×72（21）4.25-3-（2-1）（7）187.7×11-187.7（15）43×+57.125×-0.5（22）2.42÷+4.58×-4÷3．
解：（1）=1125-（997+3）+3==128；（2）12-（1+2）=--=；（3）（-）×12=×12-×12=4-2=2；（4）4.35+4.25+3.65+3.75=（4.35+3.65）+（4.25+3.75）=8+8=16；（5）17-3-4=--=；（6）22.3-2.45-5.3-4.55=22.3-5.3-（2.45+4，55）=17-7=10；（7）187.7×11-187.7=118.7×（11-1）=118.7×10=1187；（8）998+1246=（998+2）+1246-2==2244；（9）400÷125÷8=400÷（125×8）=400÷1000=0.4；（10）1×2×=××=；（11）34×（2+）=34×2+34×=68+13=81；（12）3.4×99+3.4=3.4×（99+1）=3.4×100=340；（13）÷2+×=（+）×=1×=；（14）（++）×72=×72+×72+×72=66+28+15=109；（15）43×+57.125×-0.5=（43.875+57.125）×0.5-0.5=101×0.5-0.5=50.5-0.5=50；（16）4+3.2+5+6.8=（+）+（3.2+6.8）=10+10=20；（17）25×（37×8）=25×8×37=200×37=7400；（18）125×8.8=125×8+125×0.8==1100；（19）17.15-8.47-1.53=17.15-（8.47+1.53）=17.15-10=7.15；（20）0.125×0.25×32=（0.125×8）×（0.25×4）=1×1=1；（21）4.25-3-（2-1）=（4.25+）-（+）=6-6=0；（22）2.42÷+4.58×-4÷3=（2.42+4.58-1）×=6×=8；分析：根据加法和乘法的运算定律，减法、除法的运算性质，及加减法的速算方法进行计算．点评：此题主要考查，利用运算定律、运算性质进行小数、分数四则混合运算的简便计算．
科目：小学数学
（8）998+1246
（16）4+3.2+5+6.8
（2）12-（1+2）
（9）400÷125÷8
（17）25×（37×8）
（3）（-）×12
（10）1×2×（11）34×（2+）
（18）125×8.8
（4）4.35+4.25+3.65+3.75
（12）3.4×99+3.4
（19）17.15-8.47-1.53
（5）17-3-4
（13）÷2+×
（20）0.125×0.25×32
（6）22.3-2.45-5.3-4.55
（14）（++）×72
（21）4.25-3-（2-1）
（7）187.7×11-187.7
（15）43×+57.125×-0.5
（22）2.42÷+4.58×-4÷3．
科目：小学数学
题型：阅读理解
（1）438+203
（2）256+199
（3）416-302
（4）325-198
（5）278+498
（6）3.6+2.7+6.4+7.3
（8）1.3+4.25+3.7+3
（10）5-1.4-1.6
（11）30-8.12-4.13-7.75
（13）4.3-2.45+5.7-6.55
（14）125×48
（15）25×32
（16）35×1.4
（17）1.25×88
（18）0.25×444
（19）32×0.25×12.5
（20）25×80×0.04×125
（21）1.9×4×0.5
（22）25×1.25×4×0.8
（23）（1.6+1.6+1.6+1.6）×2.5
（24）（0.7+0.7…+0.7）×12.5（80个0.7相加）
（24）9.9×8.6+8.6
（25）99×5.4
（26）4.8×1.01
（27）95×101-95
（28）95×102-190
（29）95.6×18+0.4×18
（30）（-+）×12
（31）（+-）÷
（32）24×（+-）
（33）24÷（+-）
（34）1.25×3.6+1.25×+
（35）3.3×+0.75×+75%
（36）×6.6+7.5×
（37）9.56×180-95.6×8
（38）4.8×37+47×6.3
（39）9.5×8.8+0.12×95
（40）×21
（41）×33
（44）÷42
（45）6×0.75+5×-3÷4
（46）5.4÷1.2÷5
（47）270÷18
（48）120÷（1.2×4）
（49）73÷0.8÷12.5
（50）16÷2.5
（51）48÷1.25
（52）-（-）+
（53）84-（54-16）
（54）84-（54+16）
（56）3.6×31.4+43.9×6.4
（57）（+）×
（58）×+÷
（60）×-×
（61）×÷×
（62）-×-
（63）×[÷（+）]
（64）（0.9+5）×3+2.3
（65）56×
（66）+÷+
（67）（+）÷（+）
（68）÷（-）
（69）（-）÷
（70）7.2÷（5-0.75-0.25）
（71）6.4+3.6÷0.5+4.5
（72）（6.4+3.6）÷0.5+4.5
（73）495÷55+495÷45
（74）8÷0.4+8÷1.6
（75）0.9+99×0.9
（76）5.28-（1.62+2.28）
（78）4×（+）
（80）2-（+）-
（81）×+×
（82）×+×
（83）×9+
（84）（5+）×
（85）（+）×24
（86）（20+）×
（87）×39×
（88）×（+）
（89）（-）×12
（90）×（26×）
（92）17×-
（93）（+）×
（94）（+）÷
（95）（+）÷3
（96）（-）÷
（97）÷+÷
（98）×（10+）
（99）（21+）÷
（100）×+×
（101）÷+÷
（102）（-）÷
（103）×++
（104）_×-
（105）-（÷+）
（106）+×+
（107）1-÷-
（108）×+÷4
（109）5-（4+）
（111）7.46-0.83-2.17
（112）12.85-1.17-8.83+1.15
（113）4.5×102
（114）0.4×6.3×25
（115）（4.9+4.9+…+4.9）×2.5（16个4.9相加）
（116）7.5×199
（117）（+）×36
（118）1.2×5.7-1.2+5.3×1.2
（119）0.825×102-82.5
（120）46×
（121）560÷16÷5
（122）3÷2.5
（123）84+（54-16）
（124）+++
（125）-（÷+）
（126）3×（+）+
（127）7.2÷（5-0.75+0.25）
（128）725÷25+275÷25
（129）××
（130）×45-÷
（131）48×（-）
（132）×+×
（133）（32+）÷4
（134）÷÷
（135）46×
（136）×+÷9
科目：小学数学
1.3+4.25+3.7+3.75=
17.15-（3.5-2.85）=
3.4×99+3.4=
4.8×1.01=
0.4×（2.5÷73）=
（1.6+1.6+1.6+1.6）×25&&&&&&&
12.3-2.45-5.7-4.55=
0.125×0.25×64=
64.2×87+0.642×1300=
78×36+7.8×741-7=
×+0.125×+0.5=
2.42÷+4.58×-4÷3=
4.25-3-（2-1）=
3.8÷3.9+3.9÷0.1+0.1÷3.9=
12.1-（+）×105=
科目：小学数学
（1）×[+（&-0.25）]
（2）×+÷
（3）1.8÷2.7-17÷51
（4）99.9×99+99.9&&&&&
（5）15.8-+14.2-
（6）3×9×（+）
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请输入手机号Polymorphs of 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazole-5-yl)-5,6-dihydrobenzo[F]imidazo [1,2-D][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide, methods of production, and pharmaceutical uses thereof
United States Patent 9266903
The present invention relates to crystalline polymorphs of (2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide (GDC-0032, taselisib), methods of use, and processes of preparing thereof.
Inventors:
Stults, Jeffrey (El Granada, CA, US)
Application Number:
Publication Date:
02/23/2016
Filing Date:
12/15/2014
Export Citation:
Genentech, Inc. (South San Francisco, CA, US)
Primary Class:
International Classes:
A61K31/553; A61K45/06; C07D498/04; C07D498/06
View Patent Images:
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US Patent References:
8785626Blaquiere et al.8586574Blaquiere et al.8343955Blaquiere et al.8242104Blaquiere et al.
Foreign References:
WOA1BENZOXAZEPIN PI3K INHIBITOR COMPOUNDS AND METHODS OF USEWOA1PROCESS FOR MAKING BENZOXAZEPIN COMPOUNDS
Other References:
Rodriguez-Spong et al. Adv. Drug Delivery Rev. 56 (4.
Caira, “Crystalline Polymorphism of Organic Compounds” Topics Springer, Berlin, DE 198:163-208 (Jan. 1, 1998).
Ndubaku et al., “Discovery of 2-{3-[2-(1-Isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f] imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): A β-Sparing Phosphoinositide 3-Kinase Inhibitor with High Unbound Exposure and Robust in Vivo Antitumor Activity” J. Med. Chem. 56: (2013).
PCT ISR and Written Opinion for PCT/EP.
Primary Examiner:
Goon, Scarlett
Assistant Examiner:
Muresan, Ana Z.
Attorney, Agent or Firm:
Andrus, Alex
Parent Case Data:
CROSS REFERENCE TO RELATED APPLICATIONSThis non-provisional application filed under 37 CFR §1.53(b), claims the benefit under 35 USC §119(e) of U.S. Provisional Application Ser. No. 61/916,657 filed on 16 Dec. 2013, which is incorporated by reference in entirety.
What is claimed is:
A crystalline, mono-methanolate polymorph of (2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide designated the Form A polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 10.1, 11.2, 14.0, 18.3, 20.2, and 22.0.
The Form A polymorph of claim 1 characterized by the X-ray powder diffraction pattern shown in FIG. 2.
A crystalline, isoamyl alcohol polymorph of (2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide designated the Form C polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 6.2, 14.1, 17.2, 18.3, 21.9, and 26.7.
The Form C polymorph of claim 3 characterized by the X-ray powder diffraction pattern shown in FIG. 13.
A crystalline, mono-hydrate polymorph of (2-(4-(2-(1-isopropyl-3-methyl-1-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanamide designated the Form D polymorph that exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in degrees 2-theta at approximately 12.2, 17.5, 17.7, 18.3, 20.1, 21.3, 22.8, and 26.0.
The Form D polymorph of claim 5 characterized by the X-ray powder diffraction pattern shown in FIG. 14.
A pharmaceutical composition comprising a therapeutically effective amount of the crystalline, isoamyl alcohol polymorph of claim 3, and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.
The pharmaceutical composition of claim 7 in the form of a tablet.
The pharmaceutical composition of claim 7 wherein the therapeutically effective amount is from 1 to 100 mg.
A method of therapeutic treatment a hyperproliferative disorder in a mammal comprising administering the pharmaceutical composition of claim 7 wherein the hyperproliferative disorder is selected from the group consisting of multiple myeloma, lymphoma, leukemia, prostate cancer, breast cancer, hepatocellular carcinoma, lung cancer, pancreatic cancer, and colorectal cancer.
The method of claim 10 wherein the therapeutically effective amount is from 1 mg to 100 mg.
The method of claim 10 further comprising administering a chemotherapeutic agent selected from the group consisting of 5-fluorouracil, docetaxel, eribulin, gemcitabine, cobimetinib, 5-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamide, paclitaxel, tamoxifen, fulvestrant, dexamethasone, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole.
Description:
FIELD OF THE INVENTIONThe invention relates to polymorph forms of a PI3K inhibitor compound GDC-0032, named as 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanami
de. The invention also relates to processes to obtain polymorph forms of GDC-0032 and methods of using pharmaceutical compositions of polymorph forms of GDC-0032 for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditionsBACKGROUND OF THE INVENTIONPhosphoinositide 3-kinases (PI3K) are lipid kinases that phosphorylate lipids at the 3-hydroxyl residue of an inositol ring (Whitman et al (1988) Nature, 332:664). The 3-phosphorylated phospholipids (PIP3s) generated by PI3-kinases act as second messengers recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, bringing Akt into contact with PDK1, which is responsible for activating Akt. The tumor-suppressor phosphatase, PTEN, dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation. The PI3-kinases Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al (2002) Nature Rev. Cancer 2:489; Phillips et al (1998) Cancer 83:41).The main PI3-kinase isoform in cancer is the Class I PI3-kinase, p110α (alpha) (U.S. Pat. No. 5,824,492; U.S. Pat. No. 5,846,824; U.S. Pat. No. 6,274,327). Other isoforms are implicated in cardiovascular and immune-inflammatory disease (Workman P (2004) Biochem Soc Trans 32:393-396; Patel et al (2004) Proceedings of the American Association of Cancer Research (Abstract LB-247) 95th Annual Meeting, March 27-31, Orlando, Fla., USA; Ahmadi K and Waterfield M D (2004) Encyclopedia of Biological Chemistry (Lennarz W J, Lane M D eds) Elsevier/Academic Press). The PI3 kinase/Akt/PTEN pathway is an attractive target for cancer drug development since such modulating or inhibitory agents would be expected to inhibit proliferation, reverse the repression of apoptosis and surmount resistance to cytotoxic agents in cancer cells (Folkes et al (2008) J. Med. Chem. 51:; Yaguchi et al (2006) Jour. of the Nat. Cancer Inst. 98(8):545-556). The PI3K-PTEN-AKT signaling pathway is deregulated in a wide variety of cancers (Samuels Y, Wang Z, Bardellil A et al. High frequency of mutations of the PIK3CA gene in human cancers. (2004) S 304 (; Carpten J, Faber A L, Horn C. “A transforming mutation in the pleckstrin homology domain of AKT1 in cancer” (2007) N 448:439-444).GDC-0032, also known as taselisib, RG7604, or the IUPAC name: 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanami
de, has potent PI3K activity (Ndubaku et al (2013) J. Med. Chem. 56(11):; WO ; WO ; U.S. Pat. No. 8,242,104; U.S. Pat. No. 8,343,955) and is being studied in patients with locally advanced or metastatic solid tumors (Juric et al “GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study”, 2013 (Apr. 7) Abs LB-64 American Association for Cancer Research Annual Meeting).Multiple crystal forms with different solid state properties of a drug substance can exhibit differences in bioavailability, shelf life and behavior during processing. Powder X-ray Diffraction is a powerful tool in identifying different crystal phases by their unique diffraction patternsThe pharmaceutical industry is often confronted with the phenomenon of multiple polymorphs of the same crystalline chemical entity. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattices giving the crystals different physicochemical properties. The ability to be able to manufacture the selected polymorphic form reliably is a key factor in determining the success of the drug product.Regulatory agencies worldwide require a reasonable effort to identify the polymorphs of the drug substance and check for polymorph interconversions. Due to the often unpredictable behavior of polymorphs and their respective differences in physicochemical properties, consistency in manufacturing between batches of the same product must be demonstrated. Proper understanding of the polymorph landscape and nature of the polymorphs of a pharmaceutical will contribute to manufacturing consistency.Knowledge of crystal structure at the atomic level and intermolecular interactions offer important information to establish absolute configuration (enantiomers), phase identification, quality control, and process development control and optimization. X-ray Diffraction is widely recognized as a reliable tool for the crystal structure analysis of pharmaceutical solids and crystal form identification.Availability of a single crystal of the drug substance is preferred due to the speed and accuracy of the structure determination. However, it is not always possible to obtain a crystal of suitable size for data collection. In those cases the crystal structure can be solved from X-ray powder diffraction data obtained by measurements at ambient conditions and/or at variable temperature or humidity.SUMMARY OF THE INVENTIONThe invention relates to polymorph forms of the PI3K inhibitor I (taselisib, GDC-0032, RG7604, CAS Reg. No. -4, Genentech, Inc.), named as 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanami
de, having the structure: and stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.An aspect of the invention is a pharmaceutical composition of a polymorph form of taselisib.An aspect of the invention is a method of treating a hyperproliferative disorder in a mammal with a polymorph form of taselisib.An aspect of the invention is a process for preparing a crystalline polymorph of taselisib.BRIEF DESCRIPTION OF THE DRAWINGSFIG. 1 shows an ORTEP drawing of GDC-0032 Form A—mono-methanolate solvate. Atoms are represented by 50% probability anisotropic thermal ellipsoidsFIG. 2 shows XRPD of GDC-0032 Form A, mono-methanolate.FIG. 3 shows ORTEP drawing of GDC-0032 Form B—non-solvate. Atoms are represented by 50% probability anisotropic thermal ellipsoids.FIG. 4 shows a Packing diagram of GDC-0032 viewed down the crystallographic a axis.FIG. 5 shows a Packing diagram of GDC-0032 viewed down the crystallographic b axis.FIG. 6 shows a Packing diagram of GDC-0032 viewed down the crystallographic c axis.FIG. 7 shows Hydrogen bonding in GDC-0032 as viewed down the crystallographic c axis.FIG. 8 shows Apparent π-Stacking Interaction in GDC-0032.FIG. 9 shows Calculated X-ray powder pattern of GDC-0032.FIG. 10 shows XRPD Data of GDC-0032 Form B.FIG. 11 shows Thermal Data of GDC-0032 Form B.FIG. 12 shows FT-IR (Fourier transform Infrared spectroscopy) Data for GDC-0032 Form B.FIG. 13 shows XRPD Data for GDC-0032, Form C, isoamyl alcohol.FIG. 14 shows XRPD Data for GDC-0032, Form D, mono-hydrate.FIG. 15 shows an overlay of XRPD Data of GDC-0032 Form E (top) and Form B (bottom).FIG. 16 shows an overlay of XRPD Data of GDC-0032 Form F (top) versus Form B (bottom).FIG. 17 shows an overlay of XRPD Data of GDC-0032 Form G (middle) versus Form K (top) and Form B (bottom).FIG. 18 shows an overlay of XRPD Data of GDC-0032 Form I (top) versus Form G (middle) and Form B (bottom).FIG. 19 shows an overlay of XRPD Data of GDC-0032 Pattern J1 (top) versus Form B (bottom).FIG. 20 shows an overlay of XRPD Data of GDC-0032 Pattern J2 (top) versus Form B (bottom).FIG. 21 shows an overlay of XRPD Data of GDC-0032 Pattern K (top) versus Form B (bottom).DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTIONUnless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, and are consistent with:DefinitionsThe words “comprise,” “comprising,” “include,” “including,” and “includes” when used in this specification and claims are intended to specify the presence of stated features, integers, components, or steps, but they do not preclude the presence or addition of one or more other features, integers, components, steps, or groups thereof.As used herein, the term “about” when used in reference to x-ray powder diffraction pattern peak positions refers to the inherent variability of the peaks depending on, for example, the calibration of the equipment used, the process used to produce the polymorph, the age of the crystallized material and the like, depending on the instrumentation used. In this case the measure variability of the instrument was about +-.0.2 degrees 2-theta (θ). A person skilled in the art, having the benefit of this disclosure, would understand the use of “about” in this context. The term “about” in reference to other defined parameters, e.g., water content, Cmax, tmax, AUC, intrinsic dissolution rates, temperature, and time, indicates the inherent variability in, for example, measuring the parameter or achieving the parameter. A person skilled in the art, having the benefit of this disclosure, would understand the variability of a parameter as connoted by the use of the word about.“Polymorph”, as used herein, refers to the occurrence of different crystalline forms of a compound. Crystalline forms have different arrangements and/or conformations of the molecule in the crystal lattice. Solvates are crystal forms containing either stoichiometric or nonstoichiometric amounts of a solvent. If the incorporated solvent is water, the solvate is commonly known as a hydrate. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as solubility profiles, melting point temperatures, hygroscopicity, particle shape, density, flowability, compactability and/or x-ray diffraction peaks. The solubility of each polymorph may vary, thus, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predictable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3:33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58:911 (1969); “Polymorphism in Pharmaceutical Solids, Second Edition (Drugs and the Pharmaceutical Sciences)”, Harry G. Brittain, Ed. (2011) CRC Press (2009); and J. K. Haleblian, J. Pharm. Sci., 64, ), all of which are incorporated herein by reference.The acronym “XRPD” means X-ray powder diffraction, an analytical technique which measures the diffraction of X-rays in the presence of a solid component. Materials which are crystalline and have regular repeating arrays of atoms generate a distinctive powder pattern. Materials with similar unit cells will give powder patterns that are similar in position as measured in ° 2θ (theta). Solvates which exhibit this property are called isostructural or isomorphous solvates. The intensity of the reflections vary according to the electron density causing diffraction as well as sample, sample preparation, and instrument parameters. Analysis of XRPD data is based upon the general appearance of the measured powder pattern(s) with respect to the known response of the X-ray diffraction system used to collect the data. For diffraction peaks that may be present in the powder pattern, their positions, shapes, widths and relative intensity distributions can be used to characterize the type of solid state order in the powder sample. The position, shape and intensity of any broad diffuse scatter (halos) on top of the instrumental background can be used to characterize the level and type of solid state disorder. The combined interpretation of the solid state order and disorder present in a powder sample provides a qualitative measure of the macro-structure of the sample.The terms “treat” and “treatment” refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the growth, development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.The phrase “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. In the case of cancer, the therapeutically effective amount of the drug may reduce the nu r inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration in inhibit (i.e., slow to some extent and preferably stop) inhibit, to some extent, and/or relieve to some extent one or more of the symptoms associated with the cancer. To the extent the drug may prevent growth and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR).The terms “cancer” and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, as well as head and neck cancer. Gastric cancer, as used herein, includes stomach cancer, which can develop in any part of the stomach and may spread throughout the stomach particularly the esophagus, lungs, lymph nodes, and the liver.The term “hematopoietic malignancy” refers to a cancer or hyperproliferative disorder generated during hematopoiesis involving cells such as leukocytes, lymphocytes, natural killer cells, plasma cells, and myeloid cells such as neutrophils and monocytes. Hematopoietic malignancies include non-Hodgkin's lymphoma, diffuse large hematopoietic lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, multiple myeloma, acute myelogenous leukemia, and myeloid cell leukemia. Lymphocytic leukemia (or “lymphoblastic”) includes Acute lymphoblastic leukemia (ALL) and Chronic lymphocytic leukemia (CLL). Myelogenous leukemia (also “myeloid” or “non-lymphocytic”) includes Acute myelogenous (or Myeloblastic) leukemia (AML) and Chronic myelogenous leukemia (CML).A “chemotherapeutic agent” is a biological (large molecule) or chemical (small molecule) compound useful in the treatment of cancer, regardless of mechanism of action. Chemotherapeutic agents include, but are not limited to, 5-FU, docetaxel, eribulin, gemcitabine, GDC-0973, GDC-0623, paclitaxel, tamoxifen, fulvestrant, dexamethasone, pertuzumab, trastuzumab emtansine, trastuzumab and letrozole.The term “mammal” includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs and sheep.The term “package insert” is used to refer to instructions customarily included in commercial packages of therapeutic products, that contain information about the indications, usage, dosage, administration, contraindications and/or warnings concerning the use of such therapeutic products.The phrase “pharmaceutically acceptable salt” as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate “mesylate”, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.The desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art. For example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. Acids which are generally considered suitable for the formation of pharmaceutically useful or acceptable salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences () 1 19; P. Gould, International J. of Pharmaceutics ( 217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New Y Remington's Pharmaceutical Sciences, 18th ed., (1995) Mack Publishing Co., Easton Pa.; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.The phrase “pharmaceutically acceptable” indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water.The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.The term “stereoisomers” refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.“Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis and chromatography.“Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New Y and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. The compounds of the invention may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.Polymorphs of GDC-0032The present invention includes polymorphs of GDC-0032, and processes, methods, and reagents for the production of polymorphs of GDC-0032, shown as Formula I (Roche RG7604, CAS Reg. No. -4): and named as: 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanami
de (U.S. Pat. No. 8,242,104; WO
which are expressly incorporated by reference). As used herein, GDC-0032 includes all stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof.The triclinic cell parameters and calculated volume for GDC-0032 Form B at 150K are: a=9.7944(14), b=10.4767(11), c=12.5994(17) ?, α=96.145(10), β=95.749(11), β=115.072(9)°, V=) ?3. The formula weight of the asymmetric unit in the crystal structure of GDC-0032 Form B is 460.541 amu. (formula unit)-1 with Z=2, resulting in a calculated density of 1.33 g cm-3. The space group was determined to be P-1(no. 2). A summary of the crystal data and crystallographic data collection parameters are provided in Table 8 of Example 13.The quality of the structure obtained is moderate, as indicated by the R-value of 0.060 (6.0%). Usually R-values in the range of 0.02 to 0.05 are quoted for the most reliably determined structures (Glusker, Jenny P Trueblood, Kenneth N. Crystal Structure Analysis: A Primer, 2nd ed.; Oxford University press: New York, (1985), p. 87).An ORTEP drawing of GDC-0032 is shown in FIG. 3. There is conformational disorder at C6 with the carbon partially occupying two different positions (31.3% for C6A and 68.7% % for C6B). The molecule observed in the asymmetric unit of the single crystal structure is consistent with the Formula I molecular structure. The asymmetric unit shown in 3 contains one GDC-0032 molecule.Packing diagrams viewed along the a, b, and c crystallographic axes are shown in FIGS. 4, 5, and 6 respectively. There are no solvent accessible voids. Hydrogen bonding is viewed in FIG. 7. The hydrogen bonding forms a head to tail dimer with the amide N108 acting as the hydrogen donor and triazine N25 acting as the acceptor (numbering scheme from FIG. 3). The donor acceptor distance is 2.965 (5) ? and the donor-hydrogen-acceptor bond angle is 153 (3)°. There is also an apparent intermolecular π-stacking (pi-stacking) interaction in the GDC-0032 dimer between the benzene ring of one molecule and the imidazole ring of a second molecule (FIG. 8).FIG. 9 shows a calculated XRPD pattern of GDC-0032 Form B generated from the single crystal data. The experimental XRPD pattern of GDC-0032 Form B is shown in FIG. 10. The calculated powder pattern from the single crystal data and the experimental pattern were obtained at 150° C. and approximately 295° C., respectively. Due to the temperature differences, anisotropic expansion or contraction of the unit cell parameters, a, b, c and angles α, β, γ may occur causing shifting of the reflections in the two patterns relative to one another. All the reflections in the experimental pattern are represented in the calculated pattern, indicating that the bulk material is likely a single phase and that it is the same phase as the single crystal.Form B polymorph positional parameters and their estimated standard deviations (Table 1), anisotropic temperature factor coefficients (Table 2), bond distances (Table 3), bond angles (Table 4), hydrogen bonds and angles (Table 5) and torsion angles (Table 6) are shown below.TABLE 1Positional Parameters and Their Estimated Standard Deviationsfor GDC-0032AtomxyzU(?2)O70.7024(3)0.7667(2)0.41140(17)0.0891(8)O1071.1887(2)0.6160(2)1.08382(14)0.0737(8)N10.4169(2)0.30869(19)0.31813(14)0.0508(7)N40.4357(2)0.51095(19)0.27035(15)0.0542(7)N220.1519(2)0.0206(2)0.24411(16)0.0582(7)N230.0149(2)-0.0888(2)0.19615(17)0.0647(8)N250.0383(2)0.1160(2)0.14412(15)0.0542(7)N1031.1834(2)0.6862(2)0.81079(15)0.0577(7)N1041.2508(2)0.8142(2)0.77766(16)0.0643(8)N1081.0902(3)0.7417(3)0.9983(2)0.0649(9)C20.2915(2)0.2825(2)0.24398(17)0.0483(7)C30.3022(3)0.4056(2)0.21343(19)0.0556(8)C50.4831(4)0.6616(3)0.2687(3)0.0820(11)C80.7329(3)0.6613(3)0.44724(19)0.0560(8)C90.8576(3)0.7088(3)0.52835(19)0.0602(9)C100.9019(3)0.6174(3)0.57593(17)0.0531(8)C110.8179(3)0.4731(3)0.5377(2)0.0642(9)C120.6938(3)0.4251(3)0.4580(2)0.0620(9)C130.6444(2)0.5158(2)0.41105(17)0.0496(8)C140.5014(2)0.4474(2)0.33361(17)0.0484(8)C210.1639(2)0.1420(2)0.21120(17)0.0489(8)C24-0.0481(3)-0.0253(3)0.13802(19)0.0562(9)C6A0.5737(15)0.7493(11)0.3616(14)0.076(4)C6B0.6436(8)0.7536(4)0.3075(5)0.0656(17)C1011.0309(3)0.6696(3)0.66476(18)0.0542(8)C1021.0522(3)0.5993(3)0.74523(19)0.0586(8)C1051.1579(3)0.8020(3)0.68971(19)0.0627(9)C1061.2509(3)0.6563(3)0.9095(2)0.0625(10)C1071.1696(3)0.6683(3)1.00426(18)0.0565(8)C1091.4176(3)0.7654(4)0.9414(3)0.0954(15)C1101.2387(4)0.5065(4)0.8879(3)0.0870(16)C2210.1691(6)-0.1106(5)0.3898(4)0.137(2)C2220.2569(3)-0.0047(3)0.3217(2)0.0717(11)C2230.3589(5)-0.0450(5)0.2628(3)0.115(2)C241-0.2040(3)-0.1027(3)0.0734(2)0.0695(10)H1811.068(3)0.772(3)0.943(2)0.064(8)*H1821.049(4)0.754(4)1.056(3)0.108(13)*Starred atoms were refined isotropicallyUeq = ( 1/3 )ΣiΣj Uija*ia*jai.aj TABLE 2Anisotropic Temperature Factor Coefficients - U's for GDC-0032NameU(1,1)U(2,2)U(3,3)U(1,2)U(1,3)U(2,3)O70.0980(15)0.0574(10)0.0962(14)0.0304(10)-0.0364(12)0.0128(9)O1070.0893(13)0.0883(13)0.0585(10)0.0534(11)-0.0008(9)0.0224(9)N10.0483(10)0.0536(10)0.0500(10)0.0240(9)-0.0029(8)0.0100(8)N40.0523(11)0.0524(10)0.0569(11)0.0234(9)-0.0044(8)0.0150(8)N220.0576(12)0.0537(11)0.0586(11)0.0240(9)-0.0077(9)0.0082(8)N230.0633(13)0.0528(11)0.0672(12)0.0194(10)-0.0044(10)0.0067(9)N250.0452(10)0.0576(11)0.0573(11)0.0225(9)-0.0025(8)0.0099(8)N1030.0472(10)0.0680(12)0.0529(11)0.0225(9)-0.0036(8)0.0121(9)N1040.0547(12)0.0662(13)0.0590(12)0.0171(10)-0.0041(9)0.0106(9)N1080.0719(15)0.0771(14)0.0573(13)0.0438(12)0.0015(11)0.0183(11)C20.0447(11)0.0568(12)0.0454(11)0.0254(10)0.0010(9)0.0085(9)C30.0484(12)0.0618(13)0.0562(13)0.0258(11)-0.0058(10)0.0143(10)C50.0757(18)0.0572(15)0.100(2)0.0209(14)-0.0220(16)0.0287(14)C80.0535(13)0.0580(13)0.0566(13)0.0254(11)-0.0002(10)0.0142(10)C90.0562(14)0.0558(13)0.0589(14)0.0189(11)-0.0058(11)0.0083(10)C100.0473(12)0.0630(13)0.0462(11)0.0233(11)0.0000(9)0.0083(10)C110.0641(15)0.0619(14)0.0653(15)0.0313(12)-0.0117(12)0.0097(11)C120.0613(15)0.0546(13)0.0647(14)0.0268(12)-0.0128(11)0.0040(11)C130.0460(12)0.0578(12)0.0447(11)0.0242(10)-0.0003(9)0.0084(9)C140.0473(12)0.0549(12)0.0466(11)0.0265(10)0.0025(9)0.0103(9)C210.0479(12)0.0542(12)0.0465(11)0.0251(10)0.0018(9)0.0098(9)C240.0510(13)0.0597(14)0.0552(13)0.0239(11)0.0028(10)0.0051(10)C6A0.065(7)0.064(5)0.094(9)0.030(5)-0.006(6)0.009(5)C6B0.075(3)0.050(2)0.063(3)0.022(2)-0.009(2)0.0162(17)C1010.0486(12)0.0620(13)0.0487(12)0.0239(11)-0.0007(9)0.0059(10)C1020.0466(12)0.0621(14)0.0595(13)0.0195(11)-0.0054(10)0.0105(11)C1050.0583(14)0.0671(15)0.0542(13)0.0213(12)-0.0029(11)0.0134(11)C1060.0512(13)0.0807(17)0.0585(14)0.0338(13)-0.0041(11)0.0146(12)C1070.0525(13)0.0615(13)0.0521(12)0.0255(11)-0.0087(10)0.0093(10)C1090.0487(15)0.136(3)0.085(2)0.0260(17)-0.0121(14)0.036(2)C1100.112(3)0.106(2)0.0761(19)0.079(2)0.0115(18)0.0190(16)C2210.147(4)0.145(4)0.124(3)0.059(3)0.004(3)0.082(3)C2220.0754(18)0.0585(14)0.0771(17)0.0307(13)-0.0162(14)0.0158(12)C2230.093(3)0.142(3)0.132(3)0.075(3)-0.006(2)0.032(3)C2410.0513(14)0.0711(16)0.0720(16)0.0178(12)-0.0009(12)0.0035(13)The form of the anisotropic temperature factor is: exp[-2π h2a*2U(1,1) + k2b*2U(2,2) + l2c*2U(3,3) + 2hka*b*U(1,2) + 2hla*c*U(1,3) + 2klb*c*U(2,3)] where a*, b*, and c* are reciprocal lattice constants. TABLE 3Bond Distances in Angstroms for GDC-0032Atom 1Atom 2DistanceAtom 1Atom 2DistanceO7C6A1.280(10)C11C121.367(3)O7C6B1.345(5)C11H110.950O7C81.369(3)C12C131.393(3)O107C1071.227(3)C12H120.950N1C141.312(3)C13C141.467(3)N1C21.373(3)C24C2411.487(3)N4C31.364(3)C6AH6A10.990N4C141.367(3)C6AH6A20.990N4C51.447(3)C6BH6B10.990N22C211.342(3)C6BH6B20.990N22N231.366(3)C101C1021.365(3)N22C2221.473(3)C101C1051.391(3)N23C241.313(3)C102H1020.950N25C211.327(3)C105H1050.950N25C241.347(3)C106C1101.515(4)N103C1021.341(3)C106C1071.523(4)N103N1041.354(3)C106C1091.524(4)N103C1061.476(3)C109H10A0.980N104C1051.320(3)C109H10B0.980N108C1071.307(3)C109H10C0.980N108H1810.84(3)C110H11A0.980N108H1820.89(4)C110H11B0.980C2C31.350(3)C110H11C0.980C2C211.451(3)C221C2221.500(5)C3H30.950C221H22A0.980C5C6A1.369(12)C221H22B0.980C5C6B1.449(6)C221H22C0.980C5H5A0.990C222C2231.471(5)C5H5B0.990C222H2221.000C8C91.382(3)C223H22D0.980C8C131.391(3)C223H22E0.980C9C101.374(3)C223H22F0.980C9H90.950C241H24A0.980C10C111.380(3)C241H24B0.980C10C1011.466(3)C241H24C0.980Numbers in parentheses are standard uncertainties in the least significant digits. TABLE 4Bond Angles in Degrees for GDC-0032Atom 1Atom 2Atom 3AngleAtom 1Atom 2Atom 3AngleC6AO7C6B 44.9(7)C11C12H12118.50C6AO7C8125.4(5)C13C12H12118.50C6BO7C8121.0(3)C8C13C12115.9(2)C14N1C2105.89(18)C8C13C14127.5(2)C3N4C14107.24(18)C12C13C14116.6(2)C3N4C5123.60(19)N1C14N4110.58(18)C14N4C5128.85(19)N1C14C13121.40(19)C21N22N23109.21(18)N4C14C13128.0(2)C21N22C222130.2(2)N25C21N22109.60(19)N23N22C222120.50(19)N25C21C2124.0(2)C24N23N22102.99(19)N22C21C2126.4(2)C21N25C24103.72(19)N23C24N25114.5(2)C102N103N104111.37(19)N23C24C241122.5(2)C102N103C106127.3(2)N25C24C241123.0(2)N104N103C106121.30(19)O7C6AC5132.0(13)C105N104N103103.98(19)O7C6AH6A1104.20C107N108H181125.8(19)C5C6AH6A1104.20C107N108H182117(2)O7C6AH6A2104.20H181N108H182117(3)C5C6AH6A2104.20C3C2N1110.21(19)H6A1C6AH6A2105.50C3C2C21126.6(2)O7C6BC5120.0(5)N1C2C21123.07(19)O7C6BH6B1107.30C2C3N4106.07(19)C5C6BH6B1107.30C2C3H3127.00O7C6BH6B2107.30N4C3H3127.00C5C6BH6B2107.30C6AC5N4114.3(5)H6B1C6BH6B2106.90C6AC5C6B 41.7(6)C102C101C105103.3(2)N4C5C6B115.4(3)C102C101C10127.5(2)C6AC5H5A108.70C105C101C10129.2(2)N4C5H5A108.70N103C102C101108.3(2)C6BC5H5A 69.40N103C102H102125.90C6AC5H5B108.70C101C102H102125.90N4C5H5B108.70N104C105C101113.1(2)C6BC5H5B134.30N104C105H105123.50H5AC5H5B107.60C101C105H105123.50O7C8C9114.9(2)N103C106C110109.1(2)O7C8C13124.5(2)N103C106C107111.43(19)C9C8C13120.5(2)C110C106C107109.1(2)C10C9C8122.7(2)N103C106C109109.4(2)C10C9H9118.70C110C106C109110.4(3)C8C9H9118.70C107C106C109107.4(2)C9C10C11117.1(2)O107C107N108123.7(3)C9C10C101121.8(2)O107C107C106118.7(2)C11C10C101121.1(2)N108C107C106117.5(2)C12C11C10120.7(2)C106C109H10A109.50C12C11H11119.70C106C109H10B109.50C10C11H11119.70H10AC109H10B109.50C11C12C13123.1(2)C106C109H10C109.50H10AC109H10C109.50N22C222C221110.4(3)H10BC109H10C109.50C223C222H222107.50C106C110H11A109.50N22C222H222107.50C106C110H11B109.50C221C222H222107.50H11AC110H11B109.50C222C223H22D109.50C106C110H11C109.50C222C223H22E109.50H11AC110H11C109.50H22DC223H22E109.50H11BC110H11C109.50C222C223H22F109.50C222C221H22A109.50H22DC223H22F109.50C222C221H22B109.50H22EC223H22F109.50H22AC221H22B109.50C24C241H24A109.50C222C221H22C109.50C24C241H24B109.50H22AC221H22C109.50H24AC241H24B109.50H22BC221H22C109.50C24C241H24C109.50C223C222N22109.2(2)H24AC241H24C109.50C223C222C221114.4(3)H24BC241H24C109.50Numbers in parentheses are standard uncertainties in the least significant digits. TABLE 5Hydrogen Bond Distances in Angstroms and Angles in Degrees for GDC-0032DHAD-HA-HD-AD-H-AN108H181N250.84(3)2.18(3)2.956(5)153(3)Numbers in parentheses are standard uncertainties in the least significant digits. TABLE 6Torsion Angles in Degrees for GDC-0032Atom 1Atom 2Atom 3Atom 4AngleC6AO7C8C9-159.00(0.96)C6AO7C8C1318.03(1.02)C6BO7C8C9146.90(0.43)C6BO7C8C13-36.07(0.55)C8O7C6AC5-56.21(1.75)C8O7C6AC6B-100.44(0.73)C6BO7C6AC544.23(1.18)C8O7C6BC576.44(0.66)C8O7C6BC6A110.82(0.79)C6AO7C6BC5-34.38(0.79)C14N1C2C31.11(0.26)C14N1C2C21-175.14(0.20)C2N1C14N4-1.08(0.25)C2N1C14C13178.22(0.19)C5N4C3C2-173.93(0.25)C14N4C3C20.04(0.27)C3N4C5C6A150.91(0.77)C3N4C5C6B-162.96(0.36)C14N4C5C6A-21.69(0.85)C14N4C5C6B24.44(0.51)C3N4C14N10.67(0.26)C3N4C14C13-178.57(0.22)C5N4C14N1174.23(0.27)C5N4C14C13-5.02(0.41)C21N22N23C24-0.77(0.26)C222N22N23C24177.11(0.23)N23N22C21N250.72(0.26)N23N22C21C2179.54(0.21)C222N22C21N25-176.89(0.23)C222N22C21C21.93(0.39)N23N22C222C221-37.09(0.36)N23N22C222C22389.49(0.32)C21N22C222C221140.29(0.31)C21N22C222C223-93.13(0.34)N22N23C24N250.59(0.29)N22N23C24C241-177.71(0.24)C24N25C21N22-0.34(0.25)C24N25C21C2-179.20(0.21)C21N25C24N23-0.17(0.29)C21N25C24C241178.12(0.24)C102N103N104C105-0.66(0.28)C106N103N104C105-178.91(0.24)N104N103C102C1010.71(0.31)C106N103C102C101178.83(0.25)N104N103C106C107101.41(0.27)N104N103C106C109-17.21(0.34)N104N103C106C110-138.10(0.26)C102N103C106C107-76.54(0.33)C102N103C106C109164.84(0.27)C102N103C106C11043.95(0.39)N103N104C105C1010.37(0.31)N1C2C3N4-0.71(0.27)C21C2C3N4175.38(0.21)N1C2C21N22-2.38(0.35)N1C2C21N25176.28(0.21)C3C2C21N22-178.00(0.24)C3C2C21N250.66(0.37)N4C5C6AO758.13(1.55)N4C5C6AC6B101.57(0.73)C6BC5C6AO7-43.44(1.12)N4C5C6BO7-64.58(0.61)N4C5C6BC6A-98.72(0.88)C6AC5C6BO734.15(0.87)O7C8C9C10178.08(0.27)C13C8C9C100.93(0.44)O7C8C13C12-179.58(0.26)O7C8C13C14-3.02(0.42)C9C8C13C12-2.71(0.38)C9C8C13C14173.85(0.24)C8C9C10C111.38(0.43)C8C9C10C101-177.56(0.27)C9C10C11C12-1.78(0.42)C101C10C11C12177.17(0.27)C9C10C101C102152.07(0.31)C9C10C101C105-25.95(0.47)C11C10C101C102-26.83(0.46)C11C10C101C105155.14(0.31)C10C11C12C13-0.10(0.46)C11C12C13C82.35(0.39)C11C12C13C14-174.60(0.25)C8C13C14N1-169.74(0.23)C8C13C14N49.44(0.38)C12C13C14N16.80(0.32)C12C13C14N4-174.02(0.23)O7C6AC6BC5147.30(0.64)C5C6AC6BO7-147.30(0.64)C10C101C102N103-178.87(0.27)C105C101C102N103-0.44(0.32)C10C101C105N104178.43(0.28)C102C101C105N1040.04(0.32)N103C106C107O107163.74(0.24)N103C106C107N108-20.22(0.36)C109C106C107O107-76.40(0.33)C109C106C107N10899.64(0.32)C110C106C107O10743.24(0.37)C110C106C107N108-140.72(0.30)Numbers in parentheses are standard uncertainties in the least significant digits. Physical form screening led to characterization of different crystalline phases, polymorphs, hydrates and solvates of GDC-0032. The solubility of GDC-0032 was determined in five solvents/solvent mixtures at two different temperatures (Example 2). A number of polymorph forms of GDC-0032 were characterized, including but not limited to the following:Form A, MethanolateForm A was observed in experiments containing methanol. It was initially characterized by analysis of solids from manual experiments. Form A is a crystalline material as determined from PLM and XRPD (FIG. 2). Thermal data (TGA) collected on Form A indicated a weight loss of 6.5% by 125° C. which is consistent with the loss of one mole of methanol (theoretical weight loss for mono-methanolate: 6.5%). DSC showed an endotherm at 105-125° C. (max) consistent with weight loss in the TGA followed by an endotherm at 257° C. which is attributed to the melt as confirmed by hot-stage microscopy. Thermal desolvation of the methanolate under nitrogen or vacuum led to the formation of Form B, albeit at reduced particle size. Slurrying Form A in the presence of water at 50° C. gave Form D, the mono-hydrate. A water slurry experiment at room temperature gave a mixture of Form A and Form D after drying. It is not clear if the damp material was a mixture of forms or a mixed hydrate-methanolate solvate. In addition, a partially desolvated Form A contained 0.6 moles of methanol. Single crystal structure determination on solids crystallized from methanol confirmed the Form A is a mono-methanolate. FIG. 1 shows an ORTEP drawing of GDC-0032 Form A—mono-methanolate solvate.Form B, Non-SolvateForm B is a non-solvated form derived from multiple solvents and by desolvation of multiple solvates. Form B can be prepared by heating samples of the solvated forms further described in this pattern at 10° C./minute in the DSC under nitrogen. Form B is crystalline by XRPD (FIG. 10) and by PLM (Polarized Light Microscopy). FIG. 11 shows that thermal analysis (TGA) of Form B indicated little or no weight loss up to 200° C. A small weight loss, typically less than 0.5%, was observed between 200 and 270° C. probably associated with inclusion of the crystallizing solvent in the crystals. DSC analysis indicated a single endothermic event was present at 257° C. attributed to the melt. DVS data of Form B demonstrated low kinetic hygroscopicity with less than 0.3% weight gain at 95% RH. Little hysteresis was observed on the desorption cycle. The material was still Form B after the DVS experiment. Slurrying Form B in water, with and without Tween 80, gave no conversion to the hydrate. Form B was unchanged after accelerated stability tests at 40° C. and 75% RH. FIG. 12 shows the FT-IR spectrum of Form B. Single crystal structure determination confirmed that Form B is not solvated or hydrated.Form B polymorph was selected for development based on criteria including: a propensity to form a polymorph, as opposed to a pseudo-polymorph, crystallinity, thermoanalytical data, e.g. melting point, hygroscopicity, physical stability, chemical stability in solid state, solubility, mechanical stress, powder properties, large scale manufacturability, and formulation aspects.Form C, Mono Isoamyl Alcoholate SolvateForm C was derived only from isoamyl alcohol and was initially formed at 5° C. It is crystalline by XRPD (FIG. 13) and PLM. It is isomorphous with Form V. TGA data on a non-dried, wet sample, shows a total weight loss of 15%. This weight loss was divided into two broad steps: a 5.2% weight loss was observed from ambient to 105° C. and an additional 9.8% weight loss was observed from 105-125° C. (bp of isoamyl alcohol: 130° C.). The theoretical weight loss for a mono-solvate is 16.1% and 8.7% for a hemi-solvate. The crystal structure of Form C was solved. Form C is the mono-isoamyl alcoholate. Desolvation of Form C under vacuum at 60° C. gave non-solvated Form B. DSC data indicate a strong, sharp endotherm at 109° C. followed by a strong endotherm, presumably the melt of Form B, at 257° C. It is not known if the endotherm at 109° C. is the incongruent melt of the solvate and/or the concurrent conversion to Form B. Slurry interconversion experiments with Form B in pure isoamyl alcohol indicated that Form B was preferred at temperature of approximately 20° C. or above. The solvate, Form C, was favored at temperatures of 15° C. or below.Form D, Mono-HydrateForm D is a hydrate derived from aqueous solvents at high water activity. It was not observed from Form B in the presence of pure water, water containing tween, or by gently grinding the material is the presence of water at either ambient or 60° C. Form D is crystalline by XRPD (FIG. 14) and PLM. Thermal data (TGA) indicated a weight loss of 3.7% (monohydrate theoretical 3.3%) up to 100° C. A series of isothermal TGA runs were conducted to de-risk potential wet granulation issues. Dehydration was complete on the TGA within 15 minutes at 100° C. and within 40 minutes at 60° C. DSC data indicated an endotherm at 94° C. (onset) corresponding to weight loss in the TGA. An apparent overlapping melt-recrystallization was observed at 137 and 150° C. respectively followed by melting, of Form B, at 257° C. No further work to characterize these transitions was done. Single crystal structure determination was conducted and confirms that Form D is the mono-hydrate.Form E, Mono-TrifluoroethanolateForm E was derived from 2,2,2-trifluoroethanol containing solvent systems and determined to be crystalline by XRPD. The XRPD data of Form E is given in FIG. 15. Thermal data of Form E indicated a weight loss of 18.1% up to a temperature of 160° C. (theoretical weight loss for mono-trifluoroethanolate: 17.8%). The weight loss was identified by TG-MS as 2,2,2-trifluoroethanol. DSC indicated the presence of a broad endotherm at 122° C. associated with desolvation as well as a sharp strong endotherm at 257° C. The endotherm at 257° C. is due to the melting of Form B. Single crystal structure elucidation confirmed that Form E is the mono-trifluoroethanolate.Form F, Mono Acetonitrile SolvateForm F was derived from acetonitrile and ethanolic acetonitrile. Form F is crystalline as shown by XRPD. The XRPD data of Form F is shown in FIG. 16. TGA indicated a weight loss of 7.7% at a temperature up to 240° C. (theoretical weight loss for mono acetonitrile solvate: 8.2%). The weight loss was identified as ethanol and acetonitrile by TG-MS. DSC analysis indicated a broad endotherm at 124° C. associated with the weight loss in the TGA, followed by a strong endotherm at 252° C. is due to the melting of Form B. Single crystal structure elucidation confirmed that Form F is the mono-acetonitrile solvate. Although Form F is designated as the mono-acetonitrile solvate based on the single crystal data, the TG-MS data indicates that there may be an isomorphic mixed ethanol-acetonitrile solvateForm G, Mono-EthanolateForm G was derived from ethanol and shown to be crystalline by XRPD (FIG. 17) and is essentially isomorphic with Form E, Form I, Form K, and Form L. Thermal data (TGA) indicated a weight loss of 9.6% at a temperature up to 160° C. (theoretical weight loss for monoethanolate: 9.1%). The weight loss was identified as ethanol by TG-MS. DSC analysis indicated a broad endotherm at 117° C. associated with the loss of ethanol followed by a strong endotherm at 256° C. In separate experiments, it was demonstrated that Form G converted to Form B upon heating under reduced pressure. Form G is the mono-ethanolate of GDC-0032 and is isomorphic with the trifluoroethanol solvate, Form E, which the crystal structure has been determined.Form H, Mono-Chloroform SolvateForm H is the mono-chloroform solvate of GDC-0032. This form was prepared from chloroform. The material is crystalline by XRPD as shown in Figure VV. TGA analysis indicated a weight loss of about 19.4% which corresponds to about 1 mole of chloroform. The structure of the solvate was identified by single crystal structure elucidation. Chloroform molecules occupy channels in the structure.Form I, Mono-Tetrahydrofuran SolvateForm I was derived from tetrahydrofuran (THF) and found to be crystalline by XRPD and essentially isomorphic with Form E and Form G (FIG. 18). Thermal data (TGA) indicated a weight loss of 15.0% at a temperature up to 180° C. (theoretical weight loss for mono-THF solvate: 13.5%). The weight loss was identified as THF by TG-MS. SDTA indicated a possible endotherm/exotherm combination at approximately 130° C. associated with weight loss and form conversion followed by a strong endotherm at 252° C. (max), the melt of Form B. Form I is the tetrahydrofuran solvate and is essentially isomorphic with Form E, Form G, Form K, and Form L.Form J and Pattern J MaterialsPattern J materials were derived from a cooling evaporation from acetone (Pattern J1), from acetone-water (Pattern J2), and from THF (Pattern J3). Pattern J material is crystalline by XRPD (FIGS. 19 and 20). Pattern J2 and Pattern J3 are isomorphic. The materials have been designated patterns due to the disorder in the powder patterns and the belief that the materials represent a partially desolvated structure. In addition, it is not clear what the relationship is between Form I and Pattern J3. Thermal data (TGA) for Pattern J1 indicated a weight loss of 6.8% at a temperature up to 240° C. (theoretical weight loss for hemi-acetone solvate: 5.9%, weight loss for mono-acetone solvate: 11.2%) with the majority of the weight loss occurring below 120° C. The weight loss was identified as acetone by TG-MS. TGA for Pattern J2 indicated a weight loss of 4.7% at a temperature up to 140° C. (theoretical weight loss for hemi-acetone solvate: 5.9%, weight loss for mono-acetone solvate: 11.2%) with the majority of the weight loss occurring below 100° C. The weight loss was identified as acetone by TG-MS. SDTA indicated a strong endotherm at 252° C. (max) for both patterns. The baseline in the SDTA for Pattern J2 is too noisy to draw conclusions as to potential form conversions. Pattern J3 was isolated from aqueous THF. No characterization data was collected. An isomorphic solvate (mixed solvate) of Pattern J containing THF may exist. Pattern J materials may consist of partial acetone solvates and a potential partial THF solvate.Pattern KPattern K was isolated from 2,2,2-trifluoroethanol. The material is crystalline by XRPD but appears to be less crystalline than other forms (FIG. 21). There may be a small amount of Form E present. In addition, an amorphous or defected phase may be present. Therefore this material has not been designated as a form. TGA data indicated a weight loss of 19.8% at temperatures up to 240° C. with the majority of weight loss occurring before 140° C. The majority of the material was identified by TG-MS as mainly 2,2,2-trifluoroethanol (theoretical weight loss for mono-trifluoroethanolate: 17.8%). SDTA data indicated the presence of a broad endotherm at approximately 125° C. associated with weight loss and a strong endotherm at 252° C. (max), presumably due to the melt of Form B. The material appears to consist of a mono-trifluoroethanol solvate.Form L Mono Isopropanol SolvateForm L material was isolated from isopropanol. XRPD data indicates that this material is essentially isomorphic with Form E, Form G, Form I, and Form K. TGA and DSC data demonstrate a loss of solvent and conversion to Form B. Single crystal data is given in BBB and demonstrates that Form L is the ono-isopropanol solvate.Pattern MPattern M materials were isolated from 1,2-dichloroethane (DCE)-nitromethane slurry and methyl ethyl ketone-heptane evaporation as well as a cooling experiment using 2-methyltetrahydrofuran (2-MeTHF)-heptane. There are slight differences between the powder patterns but it not known if these represent the quality of the data or if the differences represent differences between the structures of the solids. An additional material derived from 1-propanol-DCE has a similar powder pattern as the nitromethane-DCE derived material. Pattern M material from 1,2-dichloroethane-nitromethane was analyzed by TGA and DSC. TGA indicated a weight loss of 10.7% occurred by 132° C. The nature of the solvent was not identified (theoretical for hemi-dichloroethane solvate: 9.7%, theoretical for nitromethane solvate: 11.7%). DSC demonstrated a broad endotherm at 115° C. associated with weight loss in the TGA and a strong endotherm at 257° C. probably associated with the melt of Form B. Material prepared from 1-propanol was also analyzed by DSC. DSC data indicates the presence of a broad endotherm at 93° C. followed by a strong endotherm at 254° C. The broad endotherm is probably associated with weight loss but TGA data was not collected. Separate experiments using DCE and 2-Me-THF were conducted. DSC data for the DCE slurry indicated a very broad endotherm at 75° C. (onset) with two possible maxima at 85° C. and 104° C. followed by a strong endotherm at 256° C. DSC data from 2-MeTHF indicated a strong endotherm at 254° C. There may be weak transitions in the baseline but potential transitions have not been marked due to uncertainty due to the very small sample size. The broad endotherm for the DCE is probably associated with weight loss although TGA analysis was not conducted for either sample. Pattern M materials may represent a series of easily desolvated solvates.Form N Nitromethane SolvateForm N material was prepared from a long term slurry at 5° C. in nitromethane. XRPD analysis indicated the material was crystalline (Figure FF). TGA analysis indicated a 11.4% weight loss prior to 150° C. indicating the material is the mono-solvate of nitromethane. DSC analysis gave a endotherm at about 130° C. followed by the melting endotherm of Form B.Form O Carbontetrachloride Mono-SolvateForm O was prepared by slurry at 60° C. in carbon tetrachloride. The material is crystalline by XRPD (Figure WW). TGA indicated a 24.4% weight loss prior to 150° C. indicating the form is a mono-carbontetrachloride solvate. DSC analysis gave an endotherm at about 143° C. and conversion to Form B.Form P Propionitrile Mono-SolvateForm P was prepared by slurry at 60° C. in propionitrile. The material is crystalline by XRPD (Figure WW). TGA indicated a 10.2% weight loss prior to 150° C. indicating the form is a mono-propionitrile solvate. DSC analysis gave an endotherm at about 130° C. and conversion to Form B.Form Q 2-Methoxyethanol Mono-SolvateForm Q was prepared by slurry at 22° C. in aqueous 2-methoxyethanol (5% water). The material is crystalline by XRPD (Figure WW). TGA indicated a 1′3.4% weight loss in two steps indicating the form is a mono-2-methoxyethanol solvate.Form R Nitroethane Mono-SolvateForm R was prepared by slurry at 22° C. in nitroethane. The material is crystalline by XRPD (Figure WW). TGA indicated a 13.3% weight loss prior to 150° C. indicating the form is a mono-nitroethane solvate. DSC analysis gave an endotherm at about 116° C. and conversion to Form B.Form S 1,2-Dichloroethane 1/4-SolvateForm S was prepared by slurry at 22° C. in 1,2-dichloroethane. The material is crystalline by XRPD (Figure WW). TGA indicated a 5.0% weight loss prior to 180° C. indicating the form is a 1,2-dichloroethane 1/4-solvate. DSC analysis gave an endotherm at about 179° C. and conversion to Form B.Form T 1-Propanol Mono-SolvateForm T was prepared by slurry at 5° C. in 1-propanol. The material is crystalline by XRPD (Figure WW). TGA indicated a 11.3% weight loss prior to 150° C. indicating the form is a 1-propanol mono-solvate. DSC analysis gave an endotherm at about 126° C. and conversion to Form B. Single crystal structure determination was also conducted and confirmed that Form T is the 1-propanol monosolvate (Figure VV and Table BB).Form U Isobutanol Mono-SolvateForm U was prepared by slurry at 20° C. in isobutanol. The material is crystalline by XRPD (Figure WW). TGA indicated a 13.6% weight loss prior to 150° C. indicating the form is a isobutanol mono-solvate. DSC analysis gave an endotherm at about 129° C. and conversion to Form B.Form V 2-Methyltetrahydrofuran Mono-SolvateForm T was prepared by slurry at 5° C. in 2-methyltetrahydrofuran. The material is crystalline